Interleukin-4 receptors (IL4R) are present on a wide variety of human cancer cells derived from both hematopoietic and epithelial malignancies. We have targeted IL4R on a human solid tumor xenograft with chimeric proteins composed of human IL4 (hIL4) and 2 different mutant forms of a powerful bacterial toxin, Pseudomonas exotoxin A (PE). The 2 chimeric toxins, termed hIL4-PE4E and hIL4-PE38QQR, showed specific, hIL4R-dependent and dose-dependent antitumor activities. Neither of the chimeric toxins showed antitumor potency when the ADP-ribosylation activity of the toxin was inactivated by mutagenesis. One of the chimeras, hIL4-PE38QQR, caused a complete although transient regression of established solid tumors. These observations indicate that hIL4-PE chimeric proteins should be further evaluated for the treatment of human malignancies.