In recent years, it has become apparent that introduced or novel pathogens or parasites may have a significant negative impact on endangered species. Here we examine experimentally the effect of an exotic fluke from guppies on the endangered Gila topminnow. Populations from different sources showed variable responses (although statistically non-significant) to the fluke and, in particular, the most homozygous population had high fluke infections and high subsequent mortality. Homozygotes for a MHC (major histocompatibility complex) gene had lower (although statistically non-significant) survival when infected with flukes than did heterozygotes. An inbred line from one of the populations had statistically significant lower survival and higher fluke infection than did a simultaneous outbred control. Overall, Gila topminnows appear quite susceptible to infection by the non-native fluke compared to other related species. In addition, it was shown that Gila topminnows can be infected by casual contact with infected guppies. This is another example of the potential detrimental effects of a parasite on an endangered species, a threat that may constitute a particular problem for species with low genetic variation, either in general, for important MHC genes, or for populations with a past history of inbreeding.