DA anti-Lewis and DA anti-AS2 sera have little or no specificity when tested for passive enhancement of rat renal allografts. The antisera are serologically specific in the lymphocytotoxicity test, but not by cross absorption studies. Thus, this lack of specificity must, in the first instance, be the result of antigen sharing or cross reactivity between AS2 and Lewis incompatibilities. But evidence is presented that the underlying mechanism involved is more basic than simple antigen sharing or cross reactivity. A hypothesis is presented to explain the results in light of this evidence, and the clinical implications of the work are discussed. Furthermore, studies with (Lewis × AS2)F1 to DA renal allografts showed that, paradoxically, adding AS2 incompatibilities (which themselves elicit a rejection reaction in the DA strain) to Lewis incompatibilities increased the probability of indefinite survival of untreated renal allografts. A possible explanation of these results is presented.