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We thank all collaborators involved in the PCBRisk project for their enormous effort in collection of samples and for fruitful discussion and support, especially Å. Bergman and L. Hovander (Stockholm University, Sweden), M.B.M. van Duursen (IRAS, University of Utrecht, the Netherlands), and S. Jursa (Slovak Medical University, Bratislava, Slovakia). We thank M. Gájová for her assistance with extraction and fractionation of male blood samples. This work was supported by the European Union (project no. QLK4- CT-2000-00488) and by the Czech Ministry of Agriculture (MZE 0002716201). This work was presented in part at the PCB Workshop, 13-15 June 2004, Urbana-Champaign, Illinois, USA, and at the Dioxin2004 Symposium, 6-10 September 2004, Berlin, Germany. The authors declare they have no competing financial interests. Received Polychlorinated biphenyls (PCBs) are thought to cause numerous adverse health effects, but their impact on estrogen signaling is still not fully understood. In the present study, we used the ER-CALUX bioassay to determine estrogenic/antiestrogenic activities of the prevalent PCB congeners and PCB mixtures isolated from human male serum. The samples were collected from residents of an area with an extensive environmental contamination from a former PCB production site as well as from a neighboring background region in eastern Slovakia. We found that the lowerchlorinated PCBs were estrogenic, whereas the prevalent higher-chlorinated PCB congeners 138, 153, 170, 180, 187, 194, 199, and 203, as well as major PCB metabolites, behaved as antiestrogens. Coplanar PCBs had no direct effect on estrogen receptor (ER) activation in this in vitro model. In human male serum samples, high levels of PCBs were associated with a decreased ER-mediated activity and an increased dioxin-like activity, as determined by the DR-CALUX assay. 17β-Estradiol (E 2 ) was responsible for a major part of estrogenic activity identified in total serum extracts. Significant negative correlations were found between dioxin-like activity, as well as mRNA levels of cytochromes P450 1A1 and 1B1 in lymphocytes, and total estrogenic activity. For sample fractions containing only persistent organic pollutants (POPs), the increased frequency of antiestrogenic samples was associated with a higher sum of PCBs. This suggests that the prevalent nondioxin-like PCBs were responsible for the weak antiestrogenic activity of some POPs fractions. Our data also suggest that it might be important to pay attention to direct effects of PCBs on steroid hormone levels in heavily exposed subjects. Since 1959, several thousand tons of residues from the Chemko Strážske chemical plant in the Michalovce district, Slovakia, have been deposited in the nearby river and water reservoir sediments. This has resulted in widespread contamination of the environment, leading to high human exposure. Serum PCB concentrations in subjects from six different districts of Slovakia suggest that levels are three to six times higher in subjects from the Michalovce district As a part of a large epidemiologic study, the PCBRisk project Materials and Methods Chemicals. The PCB nomenclature used here is from the International Union of Pure and Applied Chemistry (IUPAC). PCBs 74, 156, 170, 187, 199, and 203 were purchased from Ehrenstorfer (Augsburg, Germany); PCBs 28, 52, 66, 99, 101, 105, 118, 126, 138, 153, 180, and 194 were supplied by Promochem (Wesel, Germany). Purity of all compounds was > 99%. The chemical structure and nomenclature of the PCB congeners we studied is presented in Blood sampling, extraction, and clean up. We collected 150 individual male blood samples from residents of two areas of eastern Slovakia, which are differently contaminated with PCBs: the Michalovce district, where commercial PCB mixtures were produced fo