SUMMARY Immunological mechanisms of increased graft survival in “immunologically privileged” sites were defined by comparing host responses against orthotopic and alymphatic skin allografts in rats. The conventional skin grafts reject by day 8; grafts placed on alymphatic skin pedicles heal in normally, but begin by day 16 to 18 to contract inexorably until only a scar remains by day 35 to 40. Lymphocyte-mediated cytotoxicity rose significantly in spleen and draining lymph nodes 8 to 10 days after orthotopic grafting, but was absent as long as 35 days after skin transplantation to alymphatic pedicles. No significant activity in antibody-dependent lymphocyte-mediated cytotoxicity was noted in either recipient group, while complement-dependent cytotoxicity was slightly elevated 8 to 10 days postoperatively in both groups. Passive transfer of serum from recipients of alymphatic skin grafts, taken 8 and 12 days after grafting, prolonged survival of test cardiac allografts significantly, although neither control serum from recipients of orthotopic skin allografts, or serum taken 28 days after alymphatic skin grafting increased test heart survival. We conclude that prolonged survival of skin grafts on alymphatic sites may be based, at least partially, on the development of host humoral factors. The anatomical defect common to most “immunologically privileged” sites is the absence of lymphatic drainage. When an allograft is transplanted to the hamster cheek pouch, anterior chamber of the eye, or the central nervous system, host sensi-tization is delayed and graft survival prolonged (4, 6, 12). Both afferent and efferent limbs of the immune response remain at least partially intact in these sites, since eventual rejection does occur while sensitization of the host by a conventional route leads to accelerated rejection of the protected graft (2, 10, 11, 13). Skin allografts on alymphatic skin pedicles in the rat survive longer than orthotopic grafts (1, 16). The inexorable chronic rejection, which they ultimately experience, suggests that recipient sensitization must occur in areas other than the regional draining lymph nodes. Thus, in contrast to the cellular reaction to conventional grafts noted in thymus-dependent areas of regional lymph nodes and spleen ( 75), cell proliferation in response to alymphatic grafts occurs primarily in splenic B cell areas. In this study, we present evidence that prolongation of survival of alymphatic grafts may be attributable, at least in part, to enhancing activity.