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Microcystins (MCs) are toxic secondary metabolites produced by freshwater cyanobacteria. Algal bloom subsidence can stimulate MC release, which can impair liver function if orally exposed to in large doses. The purpose of this retrospective, U.S. ecological study was to determine if MC exposure represented an environmental risk factor for liver disease mortality using a socioecological approach. A longitudinal ecological substudy investigated the association between average total MCs in Lake Washington and Lake Manatee and age-adjusted chronic liver disease (CLD)/cirrhosis death rates in Brevard County and Manatee County, Florida (FL). A prediction model of total MCs was deduced by quantifying levels of nitrites and phosphates in Lake Washington and Lake Manatee. According to multiple linear regression analysis, there was a significant positive association between average total MCs and age-adjusted CLD/cirrhosis death rates in the United States. Daily sunlight and state of residence also significantly predicted U.S. liver mortality rates. Average total MCs demonstrated predictive value in reference to age-adjusted CLD/cirrhosis death rates in Brevard County, FL. Positive social change can educate the federal and state governments to improve the surveillance of MCs. Results may encourage water treatment plants in Brevard County and Manatee County, FL to monitor and manage cyanobacterial contamination in drinking water sources.