The present study was designed to investigate the hypothesis that interleukin-4 (IL-4) can induce apoptosis of human endothelial cells and to study regulatory pathways of this process. Indeed, DNA ladder assay and flow cytometry study showed that IL-4 can induce apoptosis of endothelial cells in a time- and dose-dependent manner. In addition, IL-4 markedly increased activity of caspase-3, and inhibition of this enzyme suppressed IL-4-induced apoptosis in a dose-dependent manner. These results provide the first evidence that IL-4 can induce apoptosis of human endothelial cells. In addition, the data indicate that the caspase-3-dependent pathway is critically involved in this process.