Unionid mussels were collected from three mussel beds near the confluence of the Mississippi and Illinois rivers in 2003 to evaluate concentrations of selected elements and organic compounds in three abundant species and to preliminarily investigate the relative contribution of these waterways to observed contaminant burdens. Copper (Cu), selenium (Se), and zinc (Zn) concentrations were higher and lead (Pb) concentrations were lower in Amblema plicata collected downstream of the confluence than in those collected upstream. Mean concentrations of nickel (Ni), total mercury (Hg), methylmercury (MeHg), Pb, and Zn varied by species. Concentrations of cadmium (Cd) decreased with age in A. plicata from two of three sites. Tissue concentrations of some elements, e.g., arsenic (As), Cd, Cu, Pb, Se, and Zn, were similar to or higher than those previously reported for unionid mussels from areas of contaminated sediment. Concentrations of Cd, Cu, and Zn in A. plicata were comparable to those collected from the Mississippi River approximately 450 and 900 km upstream from our study sites (Naimo et al. 1992). Although total Hg concentrations we observed were an order of magnitude lower than in that study, MeHg concentrations were above those associated with reductions in soft tissue mass in a study of Elliptio complanata (Salazar et al. 1995). A number of polychlorinated biphenyl (PCB) congeners were detected in A. plicata tissues, with 85% of detections occurring in mussels from downstream of the confluence. Concentrations of individual PCB congeners were ≤33 ng/g ww and the maximum summed PCB congener concentration was 100.2 ng/g ww. Although few persistent pesticides were detected, -hexachlorocyclohexane (HCH) was detected in each of the species collected from below the confluence of the two rivers, and in A. plicata collected above it on both the Mississippi and Illinois rivers, at a maximum concentration of 103.5 ng/g ww. Aldrin, δ-HCH and dichlorodiphenyltrichloroethane (DDT) were detected in few of the specimens collected. The findings of this preliminary investigation suggest that unionid mussels from near the confluence of the Mississippi and Illinois rivers may be at risk of negative health effects of elevated exposure to certain environmental contaminants. Studies examining the health and productivity of unionid mussels from this area appear warranted.