Per- and polyfluoroalkyl substances (PFAS) are ubiquitous toxic contaminants in aquatic environments that have serious implications for both ecological and human health. In predator and prey fish from Lake Michigan (USA), we detected PFAS at concerning levels (range, 4-187 ppb; n=204) and found strong evidence for bioaccumulation through the food web. Native and introduced salmonids occupy the top of the food web in the Laurentian Great Lakes and support a robust recreational and indigenous fishery in the lakes, thereby threatening human health. Introduced Pacific salmon also spread PFAS into naive spawning tributaries where they are angled by humans, their eggs (with 100X the PFAS concentration of somatic tissues) are consumed by resident fishes, and their carcasses are scavenged by wildlife – thereby producing the ‘PFAS Lake-Riverine Cycle’. A meta-analysis of PFAS in the biota of the Great Lakes showed a west-to-east gradient of increasing concentrations of PFAS from Lake Superior to Lake Ontario. Over the past 50 years, temporal trends also reveal that PFOS (a dominant, toxic, and persistent PFAS) has gradually decreased in Great Lakes biota since its voluntary industrial phase-out in the early 2000s. However, environmental risk and economic losses associated with PFAS will persist in the Great Lakes as new and precursor compounds enter the environment. Impacts on the Great Lakes fishery also undermine critical ecosystem services, such as local food provision (especially for the disadvantaged) and the economic benefits from recreational fishing. By converting the USEPA’s reference dose for PFOS in drinking water to fish ingestion, we calculate that the safe concentration for weekly fish consumption (~8 ounces) would be 2 ppb PFOS. In this scenario, 93% of our analyzed salmonids from Lake Michigan would be unsafe to eat (6.35 ± 0.69 ppb, mean ± SE; n=87), thereby representing a significant risk to human health and regional economies.