Major histocompatibility complex (MHC) genes were originally discovered because of their role in tissue rejection in mammals and have subsequently been implicated in the incidence of autoimmune diseases and resistance to infectious diseases. Here we present the first demonstration that a gene defined by molecular sequence in the fish MHC, specifically a class II locus, plays an important role in tissue rejection. This effect in the endangered Gila topminnows appears to be additive and depends on the number of MHC alleles shared between the host and the recipient fish of the scale transplants. In addition, there was lower success of scale transplants in MHC-matched individuals in a population with high microsatellite variation than in a population with low variation. This suggests that other loci, presumably other MHC loci, play a significant role in transplantation success in fishes, as they do in mammals.