Phosphatidylserine is an endogenous acidic phospholipid that has been shown to modulate nervous system function. In the immune system, phosphatidylserine has been shown to suppress T dependent and T independent immune responses after systemic administration of antigen and lipid. However, no studies on the possible regulation by phosphatidylserine on mucosal immunity have been undertaken. Therefore, we studied the action of phosphatidylserine on immunocompetence using orally immunized mice. Mice orally administered phosphatidylserine (25 mg/kg/day) and subsequently intubated intragastrically with sheep red blood cells showed a significant decrease in antigen-specific IgM production by splenic lymphocytes compared with controls. Furthermore, the response of splenic lymphocytes obtained from phosphatidylserine-treated, antigen-primed animals to antigen or pokeweed mitogen in proliferation assays was markedly suppressed, compared with splenic lymphocytes obtained from nontreated, antigen-primed mice. Similarly, splenic lymphocytes from phosphatidylserine-treated, antigen-primed animals cultured in the presence of antigen produced no measurable interleukin 4 and low levels of interleukin 2, whereas splenic lymphocytes from antigen-primed animals produced measurable levels of interleukin 4 and significantly higher levels of interleukin 2. By fluorescence-activated cell sorter analysis, brightly stained B lymphocytes (Ig+) take up a larger portion of phosphatidylserine than do brightly stained T lymphocytes (Thy 1.2+). Collectively, these results point to the immunosuppressive qualities of phosphatidylserine. Given that phosphatidylserine is released upon injury and destruction of eukaryotic cells, these results suggest that phosphatidylserine may be an endogenous anti-inflammatory molecule.