Many pathogens of medical and veterinary importance have obligatory multihost life cycles. Yet, theoretical models aiming to predict patterns of pathogen reproductive success and the limited empirical data available with which to evaluate them, focus on directly transmitted microparasites. Patterns of host exploitation and the relative fitness of individual pathogen genotypes throughout the different host stages of multihost life cycles have thus remained ignored. We examined correlated responses to artificial selection of Schistosoma mansoni lines selected for high or low infection intensity in the intermediate host. Pathogen fitness in the intermediate host was strongly inversely correlated with pathogen fitness in the definitive host. Moreover, high pathogen infection intensity was associated with decreased, rather than increased, virulence to its intermediate host. These results raise important implications regarding the impact of genetic constraints on the maintenance of genetic and phenotypic polymorphisms in natural populations, the evolution and coevolution of parasite virulence and host specialization, as well as the success of host-directed control programs.