The major histocompatibility complex (MHC) plays an important role in infectious disease resistance. The presence of certain MHC alleles and functionally similar groups of MHC alleles (i.e., supertypes) has been associated with resistance to particular parasite species. Farmed and domesticated fish stocks are often depleted in their MHC alleles and supertype diversity, possibly as a consequence of artificial selection for desirable traits, inbreeding (loss of heterozygosity), genetic drift (loss of allelic diversity) and/or reduced parasite biodiversity. Here we quantify the effects of depletion of MHC class II genotype and supertype variation on resistance to the parasite Gyrodactylus turnbulli in guppies (Poecilia reticulata). Compared to the descendants of wild‐caught guppies, ornamental fish had a significantly reduced MHC variation (i.e., the numbers of MHC alleles and supertypes per individual, and per population). In addition, ornamental fish were significantly more susceptible to G. turnbulli infections, accumulating peak intensity 10 times higher than that of their wildtype counterparts. Four out of 13 supertypes were associated with a significantly reduced parasite load, and the presence of some supertypes had a dramatic effect on the intensity of infection. Remarkably, the ornamental and wildtype fish differed in the supertypes that were associated with parasite resistance. Analysis with a genetic algorithm showed that resistance‐conferring supertypes of the wildtype and ornamental fish shared two unique amino acids in the peptide‐binding region of the MHC that were not found in any other alleles. These data show that the supertype demarcation captures some, but not all, of the variation in the immune function of the alleles. This study highlights the importance of managing functional MHC diversity in livestock, and suggests there might be some immunological redundancy among MHC supertypes.