Local host immune responses to the lymphatic-dwelling filarial parasite Wuchereria bancrofti are important in the pathogenesis of the lymphangitis that leads to filarial elephantiasis. That the lymhatic endothelial cells may be important in this inflammatory process was shown by the ability of supernatants generated from filarial Ag-driven PBMC of individuals with filarial elephantiasis caused by W. bancrofti infection to up-regulate class I MHC expression on human umbilical vein endothelial cells when compared to unstimulated control supernatants from the same individual (relative fluorescence intensity = 159% ± 13.5; p < 0.001). In contrast, individuals with the same filarial infection but manifesting no lymphatic disease were unable to generate, in response to filarial Ag the cytokines required for this activation (relative fluorescence intensity = 93% ± 2.6). Supernatants induced by a non-filarial Ag (purified protein derivative) were able to effect class I MHC up-regulation in both patient groups. The same filarial Ag-driven supernatants did not cause detectable class II MHC staining on human umbilical vein endothelial cells. These results suggest a likely role for parasite Ag-driven, cytokine-mediated endothelial cell activation in the pathogenesis of lymphatic inflammatory/obstructive filarial disease.