Summary: The administration of a single injection of rabbit anti-mouse lymphocyte serum (RAMLS) to C57 adult male mice results in a profound circulating lymphopenia. The lymphocyte levels return gradually to normal over the succeeding 2 weeks. Coincident with the circulating lymphopenia, the survival of A strain skin grafts on these C57 mice is markedly prolonged. Rejection occurs when the circulating lymphocyte levels are approximately normal. The administration of C57 anti-A immune mouse serum (IMS) to recipients of RAMLS reverses the prolongation of A skin grafts on these mice. The administration of normal C57 mouse serum (NMS) has no effect on graft survival in RAMLS-treated mice. Neither NMS nor IMS has any effect on the pattern of circulating lymphocyte repopulation in RAMLS-treated mice. The survival of Balb/C skin grafts on RAMLS treated C57 mice is not affected by the administration of C57 anti-A IMS. The results support the concept that humoral antibody may act in synergism with lymphocytes in skin allograft rejection.