To evaluate the immunomodulatory effects of histamine in vivo, we analyzed an experimental syngenic tumor model using a colon adenocarcinoma cell line, CT-26, in Balb/c mice. In this model, distinct tumor growth was observed around 6 days after inoculation. Daily administration of cimetidine (0.12 mg/kg/day) significantly suppressed the increases in tumor volume and weight. On day 6 and day 7, histidine decarboxylase (HDC) activity was markedly increased. To examine the alterations in the local immune system, the cytokine expressions in the tumor tissue were measured by ribonuclease protection assay. The cytokine expression levels such as lymphotoxin-beta, tumor necrosis factor-alpha, interferon-gamma, interleukin-10, and interleukin-15 were considerably lower in tissues on day 14 than those on day 6, These decreased expressions were all restored by cimetidine. These results indicated that the effects of cimetidine on tumor growth in this model might be mediated by restoration of the decreased local cytokine expression, which exerts antitumoral effects.