Cimetidine, widely used for peptic ulcer disease, blocks type 2 histamine receptors present on immune cells, including T cells, B cells, and monocytes. As an earlier published study showed evidence of increases in CD4 cell counts due to this drug, we conducted a randomized, placebo-controlled, 8-week trial of oral cimetidine (400 mg p.o. t.i.d.) in a study involving 182 patients infected with human immunodeficiency virus (HIV). Overall, cimetidine-treated patients had a decline in CD4+ cell counts that was no different from the decline for placebo-treated persons, neither during the first 8 weeks of the trial (mean drop, 7.1% [standard error, 12.1-1.8] vs. 6.7% [standard error, 11.6-1.5]) nor during the subsequent 8 weeks of open-label administration of cimetidine. No differences were evident between the treatment groups in terms of the percentage reactive to p24 antigen at baseline, and p24 antigen concentrations did not change from baseline to the end of week 8. In summary, cimetidine is well tolerated by HIV-infected individuals but alters neither CD4+ cell counts nor at least one quantitative measure of viral load, HIV p24 antigen levels.