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86 patients with lymphoma were evaluated prospectively for clinical and laboratory evidence of recurrent varicella-zoster, herpes simplex, and cytomegalovirus infections during the first 16 mo of treatment. Cellular immunity to the viral antigens was measured by in vitro lymphocyte transformation and interferon production. Antibody titers and nonspecific measures of cellular immunity, including T-cell quantitation and transformation to phytohemagglutinin, were also assessed. The patients treated with radiation and chemotherapy had the highest incidence of reactivation of each of the viruses (15-19%). Greater susceptibility to herpes viral reactivation in these patients correlated with suppression of cell-mediated immunity to the specific virus. In individual patients, suppression of cellular immunity to the specific herpes viral antigen preceded each episode of reactivation, but recurrent infection did not occur in all patients with diminished specific lymphocyte transformation. Absence of the response appears to be a necessary but not a sufficient condition for the recrudescence of latent infection. Better preservation of cellular immunity to herpes simplex antigen during treatment was associated with infrequent reactivation of herpes simplex. In 25 patients with acute herpes zoster, uncomplicated recovery from the infection was accompanied by the development of lymphocyte transformation and interferon production to varicella-zoster antigen. Quantitation of T-cell numbers and phytohemagglutinin transformation did not correlate with the presence of viral cellular immunity in treated patients. Responses returned while T-cell numbers were low, and the recovery of phytohemagglutinin transformation often preceded recovery of the responses to viral antigens. Although some patients had deficiencies in viral cellular immunity at diagnosis, the duration of the suppression of specific antiviral responses resulting from treatment appears to be the most important factor predisposing to the recurrence of herpes infections in lymphoma patients.