The increased rate of outbreaks of infectious diseases in ecosystems is a dramatic consequence of global change, particularly when outbreaks affect important resources such as freshwater fish. However, the links between disease-inducing epizootics and widespread human impacts, including nutrient pollution and high water conductivity, in freshwater organisms are largely unexplored. We used data from extensive surveys in northeastern Spain (99,700 km2, 15 river catchments, n = 530 sites) to explore the environmental factors that singly, or in combination, are likely to influence the occurrence of the invasive parasite, Lernaea cyprinacea, after accounting for host fish characteristics. Smaller fish, lower altitudes, higher water conductivity and nutrient pollution were associated with higher probabilities of infection in 19 endemic and widely distributed fish species. We found no evidence that interactive effects among riverine stressors related to water and physical habitat quality better explained the probability of occurrence of L. cyprinacea in fish than did additive-stressor combinations. Nutrient pollution and high water conductivity were two of the major factors contributing to the increased occurrence of L. cyprinacea. Therefore, the improvement of wastewater treatment processes and agricultural practices probably would help to reduce the occurrence of this parasite among native fish.