Thyroid lobes cultured in hyperbaric oxygen were transplanted into recipients that differed from the donor in major histocompatibility complex (MHC) antigens alone (2 strain combinations), minor histocompatibility antigens alone (5 strain combinations), or both (5 strain combinations). Significant foci of lymphocytic infiltration, referred to here as a delayed type hypersensitivity reaction, were seen only if there were minor antigenic differences, and a significant number of rejections occurred only if there were both minor plus MHC antigenic differences. Thus, these results demonstrated a synergism between some minor and MHC histocompatibility antigens in the rejection of cultured allografts. Possible mechanisms of this synergism are discussed.