The B-cell, a major cellular component of humoral immunity, has been identified as a sensitive target of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The actual molecular mechanism responsible for the immunotoxic effects produced by TCDD is unclear; however, many of the biological effects produced by TCDD are thought to be mediated by the aryl hydrocarbon receptor (AhR). Using the CH12.LX B-cell line, the present studies show that inhibition of μ gene expression and IgM protein secretion by polychlorinated dibenzo-p-dioxin congeners follow a structure-activity relationship for AhR binding. Furthermore, these effects may be mediated by the two dioxin-responsive enhancer (DRE)-like sites that were identified within the Ig heavy chain 3′α-enhancer. Electrophoretic mobility shift assay-Western analysis demonstrated TCDD-induced binding of the AhR nuclear complex to both DRE-like sites as well as TCDD-induced binding of several nuclear factor-κB/Rel proteins to a κB site, which overlaps one of the DRE-like sites. Interestingly, κB binding in the AhR-deficient BCL-1 B-cells was also induced by TCDD, demonstrating an AhR-independent effect of TCDD on κB binding. Taken together, these results support an AhR/DRE-mediated mechanism for TCDD-induced inhibition of IgM expression.