Persons living with human immunodeficiency virus (HIV) are living longer; therefore, they are more likely to suffer significant morbidity due to potentially treatable liver diseases. Clinical evidence suggests that the growing number of individuals living with HIV and liver disease may have a poorer health-related quality of life (HRQOL) than persons living with HIV who do not have comorbid liver disease. Thus, this study examined the multiple components of HRQOL by testing Wilson and Cleary's model in a sample of 532 individuals (305 persons with HIV and 227 persons living with HIV and liver disease) using structural equation modeling. The model components include biological/physiological factors (HIV viral load, CD4 counts), symptom status (Beck Depression Inventory II and the Medical Outcomes Study HIV Health Survey (MOS-HIV) mental function), functional status (missed appointments and MOS-HIV physical function), general health perceptions (perceived burden visual analogue scale and MOS-HIV health transition), and overall quality of life (QOL) (Satisfaction with Life Scale and MOS-HIV overall QOL). The Wilson and Cleary model was found to be useful in linking clinical indicators to patient-related outcomes. The findings provide the foundation for development and future testing of targeted biobehavioral nursing interventions to improve HRQOL in persons living with HIV and liver disease.