Our study demonstrated that influenza vaccination for ESRD patients receiving HD was associated with lower morbidities, including total hospitalization, ICU admission, pneumonia/influenza, septicemia/bacteremia/viremia, respiratory failure, and heart disease. In addition, influenza vaccination was also associated with lower all-cause mortality risk for 50%. The mortality risk decreased further to have an overall adjusted HR of 0.30 as subjects with vaccinations for multiple years were counted. Consistent with the present study, a previous research in the US reported that the risks of hospitalization and death for HD patients vaccinated against influenza are lower than those of unvaccinated patients, with odds ratios of 0.93 (95% 0.90–0.95) and 0.77 (0.73–0.81), respectively 
. Moreover, they found that vaccination was significantly associated with lower risks of cause-specific mortality, including cardiac and infectious deaths. Recent reports demonstrated that influenza vaccination was associated with a lower mortality risk 
. The mortality hazard was reduced further for patients receiving both pneumococcal and influenza vaccinations. On the contrary, McGrath et al. recently reported little clinical benefits of influenza vaccination on preventing hospitalization and death 
. However, their study did not consider the confounding effect of pneumococcal vaccination. Therefore, our study observed closely the effectiveness of influenza vaccination, by excluding the effect of pneumococcal vaccine. In addition, these studies analyzed prevalent ESRD patients. Length of time with ESRD may have confounding effect on the outcomes.
Compared with healthy control subjects, ESRD patients possess suboptimal immune response rates but develop satisfying protection rates to influenza vaccination 
. The antibody response rates to influenza vaccination (defined as a four-fold increase in hemagglutination inhibition titers) vary from 7% to 89% 
. The seroprotection rates (defined as hemagglutination inhibition titers≥40) range from 46% to 93%, depending on the specific strain measured 
. Booster vaccination fails to improve the immune response 
. Influenza vaccination is safe without causing major adverse effects in HD patients 
, and the number of minor adverse reactions is low 
Since 1998, the Taiwan NHI program has started to offer influenza vaccinations to high-risk subjects, including ESRD patients and the elderly subjects. Majority of the vaccinated subjects receive this service annually between October 1 and December 31. However, the influenza vaccination rate in this study was low for incident HD patients, especially in the beginning years (1998 and 1999). The higher vaccination rate in 2009 was likely due to the pandemic novel influenza A (H1N1) in April 2009 
. The low vaccination rate may be attributed to the lack of awareness on its benefit, fear of adverse reactions, and lack of physician recommendation 
. The goal of the World Health Organization is to increase the annual influenza vaccination rate to 90% by 2010 for ESRD patients.
Influenza may lead to viral pneumonia and bacterial superinfection. HD patients are susceptible to pulmonary infection. Transient hypoxemia occurs during dialysis because of leukocyte migration in the pulmonary vasculature and loss of carbon dioxide 
. In addition, HD patients are exposed to other patients and medical staff. Our study demonstrated that influenza vaccination was associated with a lower risk of pneumonia/influenza during the first 3 months after vaccination (data not shown). Seroprotection was maintained at least for 3 months and up to 6 months after influenza vaccination in patients with renal diseases 
Consistent with the findings of the present study, Gilbertson reported that influenza vaccination is associated with a lower risk of heart disease in ESRD patients 
. For patients with chronic kidney disease, an association between influenza vaccination and atherosclerotic heart disease event rates also exists 
. Systemic inflammation caused by influenza infection may lead to endothelial injury, impaired vasodilatation, and enhanced thrombosis formation 
. Inflammation is highly associated with increasing cardiovascular mortality 
The current study has several limitations. First, the NHI database provided limited information on socio-demographic characteristics, with unavailable information on marital status, educational level, smoking habit, body-mass index, and laboratory data, such as hemoglobin, albumin, and residual renal function. These variables cannot be adjusted in the analysis. Furthermore, certain information on chronic conditions, such as hyperlipidemia and hypertension, were not available for some individuals. However, HD patients were visited by health care professionals frequently, the claim data were reliable. Moreover, the decision to receive vaccination may have been affected by socioeconomic status, as well as availability of health care and medical providers. Although multivariate analysis was used, selection bias may occur. Fourth, this study focused only on all-cause mortality because the cause of death cannot be obtained from the database. Finally, the strain and virulence of the predominant virus and the match between the circulating virus strain and the virus strain selected in the vaccine varied from year to year. Therefore, we adjusted the calendar year for temporal effect.