An experimental study was performed in 2009-2010 to investigate the polluting effect of eutrophic inland waters communicating with the sea coast. The study was planned after a heavy and long-lastingPlanktothrix rubescensbloom occurred in the Lake Occhito, an artificial reservoir. The waters of the reservoir flow into the southern Adriatic Sea, near several marine breeding ofMytilus galloprovincialismussels, a typical seafood from the Apulia region (Southern Italy). A monitoring study of water and mussels from the sea coast of northern Apulia region and on the Occhito reservoir was carried out over twelve months, to get more information regarding the contamination by cyanobacteria and related cyanotoxins. Elisa immunoassay analyses estimated total microcystin amounts from 1.73 to 256 ng/g in mussels, up to 0.61 μg/L in sea water and up to 298.7 μg/L in lake water. Analyses of some samples of free-living marine clams as well as of marine and freshwater fish proved microcystin contamination. Selective confirmatory analyses by LC/ESI-Q-ToF-MS/MS on some mussel samples identified the microcystin desMe-MC-RR as the major toxin; this compound has been reported in the literature as a specific marker toxin ofPlanktothrix rubescensblooms. Our study describes for the first time the direct relationship between environmental pollution and food safety, caused by seafood contamination from freshwater toxic blooms.