The effect of cimetidine, a histamine H2 receptor antagonist, was investigated in 12 healthy volunteers over a period of six weeks. Cimetidine was administered orally in a daily doses of 1,600 mg during the first three weeks of evaluation. Significant alterations in values of immunoglobulins (IgG, IgA), complement (C3), B-lymphocytes and T-helper cell counts were found after cimetidine intake. The in vitro lymphocyte proliferation response to plant mitogens was increased. In contrast to results obtained from a previous study with healthy volunteers who were given 800 mg cimetidine, we found no significant increase in the CD4/CD8 ratio and no decrease in the CD8 but a significant increase in the CD4 cell count. Whereas the peripheral blood immune system showed signs of immune system activation following 800 and 1,600 mg cimetidine intake, reactivity patterns of skin immune system, however, differed in both studies. The data suggests that cimetidine has a dose and time dependent effect on the immune system.