BACKGROUND Murine intraepithelial lymphocytes kill Giardia lambia; responses of human intestinal lymphocytes to this parasite are unknown. OBJECTIVE To examine giardia induced proliferation, interferon gamma production, migration, and cytotoxicity by lymphocytes from the human intestine and peripheral blood. METHODS Giardia were added to intraepithelial lymphocytes, lamina propria lymphocytes, and peripheral blood lymphocytes, obtained from jejunal mucosa and blood of otherwise healthy patients undergoing gastric bypass surgery for morbid obesity. Proliferation was measured by 3H-thymidine incorporation; frequency of proliferation precursors, by limiting dilution analysis; interferon gamma production, by ELISA; cytotoxicity, by 51Cr release of radiolabelled giardia and by release of serine esterases by effector lymphocytes that mediate cytotoxicity. RESULTS The CD4+ T lymphocytes from intestine and blood proliferated in response to giardia. The stimulus by the parasite was mitogenic rather than antigenic due to the fact that the peak response was on day 3 rather than day 6, and the large number of precursors was in the range of that for mitogens. CD4+ T lymphocytes from both sites produced interferon gamma in response to giardia. Lymphocytes did not migrate towards or kill the parasite. CONCLUSIONS Giardia induced the same degree of proliferation and interferon gamma production by CD4+ T lymphocytes in intestine and blood, but did not trigger cytotoxicity or migration.