A nontoxic murine model has been developed in which sensitization to allogeneic platelet transfusions in adults can be prevented. This model is based upon allogeneic liver membrane (LM) induction of specific humoral tolerance to major histocompatibility alloantigens. In normal mice of the C3H background, syngeneic and H-2-incompatible congeneic platelets had at½= 15 ± 3 hr; for mice of the C57BL background, the comparablet½was 33 ± 6 hr. Platelets of C3H background transfused into C57BL background recipients, and vice versa, hadt½midway between, 24 ± 3 and 24 ± 2 hr, respectively. These data suggest genetically determined variation in normal platelet survival. In passively immunized C3H background mice, the t½was decreased to 10 ± 2 hr. In C57BL background mice actively immunized i.p. with allogeneic lymphoid cells,t½was decreased to 18 ± 4 hr. When allogeneic LM was given concomitantly with the allogeneic cells, however, sensitization to foreign H-2 antigens was blocked, and survival of both C3H and C57BL background allogeneic platelets remained normal. These data demonstrate that in this free cell allograft system LM treatment is a safe and effective method for preventing adult sensitization to allogeneic platelets.