The survival times of B10.D2 mouse skin grafted onto B6AF1 recipients were significantly and consistently prolonged through treatment of the hosts with B6AF1 anti-B10.D2 serum. In this experimental system the grafts contain only one isoantigenic specificity, H-2.31, which is absent in the recipients' tissues. It is thus possible to suppress specifically the host response to all relevant antigens in the graft. The importance of this condition in obtaining enhancement of skin grafts was shown through the use of grafts which contained, in addition to H-2.31, other H-2 or non-H-2 antigens not present in the recipient mice. In these cases, prolongation of survival was not observed or was less striking than that observed for B6AF1 hosts. Injections of serum given on alternate days until rejection occurred were only slightly more effective than a single injection given at the time of grafting, and second set grafts were completely unaffected by antiserum. Both of these observations suggest that interference with the effector mechanisms of immunity does not play an important role in enhancement of skin grafts. Marked prolongation of graft survival was observed when recipients received total body x-irradiation (400 R) and anti-H-2.31.