Background Pilot studies have shown that histamine H2 receptor antagonists augment the natural immunity against cancer in colorectal and gastric cancer by enhancing lymphocytic infiltration in the tumors. However, a study of adjuvant ranitidine failed to show a significant benefit in colorectal cancer, possibly because of the immunosuppression exerted by blood transfusion and post-operative infections. The pre-operative use of H2 receptor antagonists may therefore be of greater benefit. Except for a pilot study using cimetidine, there are no trials that have evaluated the effect of pre-operative H2 receptor antagonists on tumor infiltrating lymphocytes in colorectal cancer. Objective To evaluate the efficacy of famotidine in augmenting tumor infiltrating lymphocytes in colorectal cancer. Study design Double blind, placebo controlled, prospective randomized study. Methods Twenty-three patients with resectable colorectal cancer were randomized to receive famotidine ( n = 11) or placebo ( n = 12). Famotidine was given for 1 week pre-operatively in a dose of 40 mg per day p.o. After resection, the specimens were analyzed histologically for lymphocytic infiltration by a pathologist blinded to the two groups. Lymphocytic infiltration more than 50 cells per high power field, involving more than 50% of the tumor-normal tissue interface was considered significant. Results The two groups were comparable for age, gender, pre-operative carcino embryonic antigen (CEA) levels and pathological stage. Significant lymphocytic infiltration was seen in 63.6% (7 of 11) patients in the study group compared to only 8.5% (1 of 12) patients in the placebo group ( P = 0.005). Despite fewer recurrences and a longer survival in the study group, the difference was not significant. Conclusion This study shows that pre-operative famotidine may significantly enhance lymphocytic infiltration in colorectal cancer and may have potential for use as an anticancer agent in colorectal cancer.