The freshwater pearl mussel Margaritifera margaritifera is an endangered species in Sweden with more than 600 known populations distributed in 16 out of 21 counties. Only approximately one-third of these populations are considered viable and healthy with signs of recent juvenile recruitment. From 2011 to 2017, research documented an increased mortality in this species, of up to 100% in some populations, but no etiological cause of these mortalities has been identified. With this paper, we provide current knowledge of locations where mass mortality of freshwater pearl mussel has been found in Sweden and discuss possible causes. Postmortem sampling and histopathological findings from two counties in 2016–17 detected lesions in digestive glands indicating a reduced capacity for nutrient uptake. Results from these macroscopic and microscopic investigations also indicate a reduction in, or a lack of, reproductive output compared with reference populations.