Microplastics are a persistent and increasing environmental hazard. They have been reported to interact with a variety of biotic and abiotic environmental stressors, but the ramifications of such interactions are largely unknown. We investigated virus-induced mortalities in a commercially important salmonid following exposure to microplastics, plastic microfibers, and natural (non-plastic) microparticles . Microplastics or microparticles alone were not lethal. Mortality increased significantly when fish were co-exposed to virus and microplastics, particularly microfibers, compared to virus alone. This presents the unique finding that microplastics (not natural microparticulate matter) may have a significant impact on population health when presented with another stressor. Further, we found that mortality correlated with host viral load, mild gill inflammation, immune responses, and transmission potential. We hypothesize that microplastics can compromise host tissues, allowing pathogens to bypass defenses. Further research regarding this mechanism and the interplay between microplastics and infectious disease are paramount, considering microplastics increasing environmental burden. • Interaction between microplastics and environmental pathogens is poorly understood. • A salmonid fish was co-exposed to virus and microplastics or natural microparticles. • Mortality increased when co-exposed to virus and microplastics, especially microfibers. • Mortality correlated with host viral burden, gill damage and inflammation. • Microplastics may increase severity of infection, necessitating further research.