Fish populations of the lower Sheboygan River, located in east-central Wisconsin, are considered impaired under the Great Lakes Water Quality Agreement between the United States and Canada. Pollutants in the Sheboygan River system include: polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), and heavy metals. This study compared general health and biochemical parameters, histology of selected organs, and contaminant residues and metabolites in a population of white suckers (Catostomus commersoni) from a contaminated reach of the Sheboygan River and an upstream reference site. Fish from the contaminated site had significantly lower hematocrits, significantly induced ethoxyresorufin-O-deethylase (EROD) activity as a measurement of hepatic mixed-function oxygenase activity, higher biliary metabolites of PAHs, and higher tissue concentrations of PCBs and p,p’-DDE relative to an upstream reference population. Analysis of covariance suggests that both PCB and PAH exposure may be influencing EROD activities. Fish from the contaminated site featured more basophilic clusters and developing nephrons in kidney tissue suggesting the presence of a nephro-toxicant. Also, more fish exhibited hepatic lesions including diffuse cellular vacuolation, multifocal coagulative necrosis, bile ductal hyperplasia, and foci of cellular alteration which may be biomarkers for contaminant impacts. This study demonstrates that white suckers residing in the lower reaches of the Sheboygan River absorbed significant amounts of PAHs and PCBs and also exhibited hematological, biochemical and histological alterations some of which suggest impaired fish condition.