BACKGROUND: Initiation of combination antiretroviral therapy may be followed by inflammatory reactions. We studied the epidemiology of herpes zoster infection among patients with human immunodeficiency virus (HIV) infection who were treated with combination antiretroviral therapy. SUBJECTS AND METHODS: Of 316 patients who initiated combination antiretroviral therapy, 24 (8%) were treated for herpes zoster within 17 weeks of starting therapy. The characteristics of these cases were compared with those of a control group of 96 HIV-1-infected patients, who were matched by age, sex, plasma HIV-1 RNA concentration and CD4 cell counts, and length of follow-up. RESULTS: The incidence of herpes zoster associated with combination antiretroviral therapy was 9 episodes per 100 patient-years. There were no significant differences between cases and controls in age, sex, years of HIV infection, history of herpes zoster, previous acquired immune deficiency syndrome, or baseline mean CD4 and CD8 cell counts before beginning combination antiretroviral therapy. However, patients who developed herpes zoster had a significantly greater mean (± SD) increase in the number of CD8 cells than did controls (347 ± 269 vs. 54 ± 331 cells/mL, P = 0.0006). In a multivariate analysis, the only factor that was associated with the development of herpes zoster was the increase in CD8 cells from before initiation of combination antiretroviral therapy to 1 month before development of herpes zoster (odds ratio 1.3 per percentage increase; 95% confidence interval: 1.1 to 1.5; P = 0.0002). CONCLUSION: The initiation of combination antiretroviral therapy in HIV-1-infected patients was often associated with the development of herpes zoster, especially in those in whom the number of CD8 cells increased after therapy. © 2001 by Excerpta Medica, Inc.