We examined the effects of lansoprazole, a proton-pump inhibitor, on peripheral blood mononuclear cells in healthy subjects in comparison with ranitidine. Ten healthy volunteers were randomly divided into two groups and given either lansoprazole (30 mg daily for 2 days) or ranitidine (150 mg daily for 21 days). Peripheral blood was collected before and 7, 14, and 21 days after the start of treatment. Mononuclear cells were isolated by densitometric centrifugation and were examined for adhesion molecules (ICAM-1, VLA4, SLe(x)), membrane markers of the monocyte/macrophage series, and lymphocyte phenotypes. The number of cells expressing adhesion molecules, the number of monocytes/macrophages, and lymphocyte phenotypes were the same in Helicobacter pylori-positive and -negative subjects. The number of cells expressing ICAM-1 was significantly decreased seven days after the start of lansoprazole treatment, and this change persisted until day 14, while ranitidine had no effect. The number of monocytes (identified by Leu-M3 positivity) was decreased seven days after the start of treatment in both groups, but predominantly in the lansoprazole group. No other changes were observed on administration of either drug. These results suggest that short-term treatment with lansoprazole causes persistent inhibition of inflammatory responses irrespective of the presence of H. pylori infection. This effect may indicate a possible new mechanism of action of proton-pump inhibitors other than inhibition of acid secretion.