Although the commercial synthesis of polychlorinated biphenyls (PCBs) has been banned in the United States for several decades, they are persistent in the environment with exposure mainly being through diet. The biologic and toxic effects of PCBs and their metabolites are due in part to their ability to interact with several cellular and nuclear receptors, thereby altering signaling pathways and gene transcription. These effects include endocrine modulation and disruption. Therefore, the natural history of cancer in tissues expressing these receptors may be modulated by PCB congeners, which are known to have estrogenic, antiestrogenic, and other hormonal effects. Several frameworks for grouping PCB congeners based on these interactions have been proposed. We conducted a hospital-based, case-control pilot study of 58 prostate cancer cases and 99 controls to evaluate the association between the proposed PCB groupings and the risk of prostate cancer. Serum samples were analyzed for a total of 30 PCBs. In multivariate analyses, the odds of prostate cancer among men with the highest concentrations of moderately chlorinated PCBs or PCBs with phenobarbital-like activities (constitutively active receptor (CAR) agonists) was over two times that among men with the lowest concentrations. Increasing trends in risk across the concentration levels were also observed. These results suggest that a higher burden of PCBs that are CAR agonists may be positively associated with an increased risk of prostate cancer and they encourage further research in this area.