Drugs and other chemicals that have the potential to induce or exacerbate systemic autoimmune diseases in humans are of great concern. The aim of this study was to examine the immune-disregulating potential of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by using the popliteal lymph node (PLN) assay. Chlorpromazine (CPZ) was used as a reference compound for 2 reasons: (a) CPZ is known to elicit a positive response in this assay, and (b) CPZ is a structural analogue of TCDD. Male Sprague-Dawley rats were injected subcutaneously with either TCDD or CPZ into the right hind footpad, whereas vehicle alone was injected into the contralateral footpad. Control rats were injected with vehicle in both hind footpads. Animals were sacrificed on day 7, and their PLNs were removed, weighed, and immersed in 10% formalin. The PLN weight index (the weight ratio of right PLN over left PLN) was significantly higher in both CPZ- and TCDD-treated rats than in controls. Histological examinations of PLNs in the CPZ- and TCDD-treated rats revealed similar morphological changes in both groups (e.g., mild follicular hyperplasia with no evidence of an acute inflammatory response). These results indicate that TCDD has the potential to induce or exacerbate autoimmune-like reactions. Results also suggest that drugs may be useful surrogates to study the mechanism of toxicity of environmental chemicals that cannot be administered to humans.