Genetic compatibility, nonspecific defenses, and environmental effects determine parasite resistance. Host mating system (selfing vs. outcrossing) should be important for parasite resistance because it determines the segregation of alleles at the resistance loci and because inbreeding depression may hamper immune defenses. Individuals of a mixed mating hermaphroditic freshwater snail, Lymnaea ovata, are commonly infected by a digenetic trematode parasite, Echinoparyphium recurvatum. We examined covariation between quantitative resistance to novel parasites and mating system by exposing snail families from four populations that differed by their inbreeding coefficients. We found that resistance was unrelated to inbreeding coefficient of the population, suggesting that the more inbred populations did not carry higher susceptibility load than the less inbred populations. Most of the variation in resistance was expressed among the families within the populations. In the population with the lowest inbreeding coefficient, resistance increased with outcrossing rate of the family, as predicted if selfing had led to inbreeding depression. In the other three populations with higher inbreeding coefficients, resistance was unrelated to outcrossing rate. The results suggest that in populations with higher inbreeding some of the genetic load has been purged, uncoupling the predicted relationship between outcrossing rate and resistance. Snail families also displayed crossing reaction norms for resistance when tested in two environments that presented low and high immune challenge, suggesting that genotype-by-environment interactions are important for parasite resistance.