Immunoregulation by lipids containing the phosphorylserine (PHS) group has been studied in rodent peritoneal mast cells and human peripheral blood lymphocytes. When PHS is linked to a phospholipid backbone (mono- and diacylglycerol), mast cell activation is produced. However, the effect decreases linking the PHS group to long chain alkanols and is abolished in cholesteryl-PHS, showing that the acylglycerol moiety participates in mast cell activation. Phospholipids containing the PHS group inhibit proliferation of activated peripheral blood lymphocytes. In contrast to mast cells, this effect is retained in alkyl-PHS and is enhanced in cholesteryl-PHS, indicating that in this case the PHS group is the main effector. Among non-phospholipid PHSs, cholesteryl-PHS has been the most interesting since it associates lack of mast cell activation and high inhibitory activity on peripheral blood lymphocytes. This selectivity suggests that this compound may have a potential as an immunosuppressive agent.