A high incidence of herpes zoster was noticed among patients with AIDS, shortly after addition of a protease inhibitor to their baseline treatment with nucleoside analogue reverse-transcriptase inhibitors. Within a median follow-up of 64 weeks (range, 34-103 weeks), 14 patients (7%) had a first episode or a recurrence of herpes zoster (6.2 episodes per 100 patient-years). No episodes of zoster were diagnosed before week 4. Twelve episodes (86%) occurred between weeks 4 and 16. The risk of zoster was independent of age, sex, type of protease inhibitor, and CD4+ lymphocyte count and viral load at baseline and month 1. A CD8+ lymphocyte proportion at baseline of>> 66% (hazard ratio [HR], 10.6; 95% confidence interval [CI], 3.4-33.1) and an increase in CD8+ lymphocyte proportion at month 1 of>> 5% (HR, 32; 95% CI, 8.1-126.4) were independently associated with the risk of herpes zoster. These data might be clinically useful for determining transient prophylaxis for those patients at high risk.