Selective skewing of autoreactive interferon-γ (IFN-γ)-producing T helper cells (Th1) toward an interleukin-4 (IL-4)-producing (Th2) phenotype can in experimental animals alleviate autoimmune disease without inducing general immunosuppression. In a prospective dose escalation study, we assessed treatment with human IL-4 (rhuIL-4) in 20 patients with severe psoriasis. The therapy was well tolerated, and within six weeks all patients showed decreased clinical scores and 15 improved more than 68%. Stable reduction of clinical scores was significantly better at 0.2–0.5 μg rhuIL-4 than at ≤0.1 μg rhuIL-4 (P = 0.009). In psoriatic lesions, treatment with 0.2–0.5 μg/kg rhuIL-4 reduced the concentrations of IL-8 and IL-19, two cytokines directly involved in psoriasis; the number of chemokine receptor CCR5⁺ Th1 cells; and the IFN-γ/IL-4 ratio. In the circulation, 0.2–0.5 μg/kg rhuIL-4 increased the number of IL-4⁺CD4⁺ T cells two- to three-fold. Thus, IL-4 therapy can induce Th2 differentiation in human CD4⁺ T cells and has promise as a potential treatment for psoriasis, a prototypic Th1-associated autoimmune disease.