Promethazine has been shown to possess definite immunosuppressive activity in clinical and experimental organ transplantation. However, there are few data concerning the mechanism of its influence on immune reactions. In the present studies promethazine was shown to inhibit natural killer cell-mediated cytotoxicity in vitro. Combined analysis of 51Cr-release and single-cell assays revealed that this agent affects some processes involved in delivering the 'lethal hit' but not the binding of target cells nor the recycling capacity of effector cells. The possible mechanism of promethazine action at the cellular level is discussed.