The effect of cimetidine, a histamine H2-receptor antagonist, on the immune system in man was investigated in 11 healthy volunteers. Cimetidine was administered orally in daily doses of 800 mg for a period of 7 days. At the end of the administration period the number of peripheral CD8+ (cytotoxic/suppressor) cells had diminished significantly (P less than 0.05) along with a corresponding increase in the CD4+ (helper/inducer): CD8+ (cytotoxic/suppressor) cell ratio (P less than 0.01). Compared with pretreatment values, a significant in vitro blastogenic response to mitogen stimulation with concanavalin A (P less than 0.005), phytohemagglutinin (P less than 0.01), and pokeweed mitogen (P less than 0.05) was observed in lymphocytes of volunteers after cimetidine intake. The cell-mediated hypersensitivity as assessed by skin testing of seven recall antigens was also enhanced significantly (P less than 0.001). Using Spearman's coefficient of correlation to compare mitogen-stimulation tests and skin tests of delayed hypersensitivity to the CD4+:CD8+ ratio, yielded a positive correlation (r = 0.89; r = 0.85, respectively). These effects were reversible 96 h after the last cimetidine dose. In contrast, leukocytes, total T lymphocytes (CD2+, CD3+), CD4+ (helper/inducer) cells, natural killer cells (Leu7+), immunoglobulins, and total complement, C3, C4 were unaffected by cimetidine administration.