Carrageenan, a high molecular weight sulphated polygalactan, is a potent inhibitor of immune responses mediated by macrophages. In the present study, spleen cells from rats orally dosed with 5 mg/kg or 50 mg/kg Seakem 9 carrageenan displayed a long-lasting depression of T lymphocyte mitogenesis as measured by [3H]-thymidine uptake in response to phytohaemagglutinin (PHA) or concanavalin A (Con A). Maximal suppression of splenic T cell proliferation occurred with the low dose (5 mg/kg) of orally administered carrageenan. Removal of adherent cells restored the PHA mitogenic response, suggesting a macrophage-mediated mechanism in suppression of lymphocyte activation. Rats which received 5 mg/kg carrageenan displayed impaired host resistance to Listeria monocytogenes as evidenced by increased numbers of Listeria in the peritoneal cavity 18 hr after i.p. inoculation. Supernatants from peritoneal exudate macrophages, as well as resident macrophages themselves obtained from carrageenan-fed rats, also suppressed PHA-induced spleen cell mitogenesis. These data support the hypothesis that low doses of orally administered carrageenan stimulate a population of macrophages to actively suppress T lymphocyte proliferation, while high doses abolish suppressor activity.