One of the characteristic features of anaplastic lymphoma kinase (ALK)(+), anaplastic large cell lymphoma (ALK(+)ALCL) is the constitutive activation of signal transducers and activators of transcription-3 (STAT3), a defect believed to be important for the pathogenesis of these tumors. In this report, we describe the existence of an autocrine stimulatory loop involving interleukin-22 (IL-22) that contributes to STAT3 activation and tumorigenicity of ALK(+)ALCL. The IL-22 receptor, a heterodimer composed of IL-22R1 and IL-10R2, was expressed in all ALK(+)ALCL cell lines and tumors examined. The expression of IL-22R1 in ALK(+)ALCL is aberrant, as this protein is absent in benign lymphocytes. Although ALK(+)ALCL cells produce endogenous IL-22, addition of recombinant IL-22 to ALK(+)ALCL cell lines significantly increased STAT3 activation, cell proliferation and colony formation in soft agar. Opposite biological effects were observed in cells treated with recombinant IL-22 binding protein (a naturally occurring IL-22 decoy) or IL-22-neutralizing antibody. Nucleophosmin (NPM)-ALK, the characteristic fusion gene oncoprotein expressed in ALK(+)ALCL, directly contributes to the aberrant expression of IL-22R1, as transfection of NPM-ALK in Jurkat cells-induced IL-22R1 expression and IL-22-mediated STAT3 activation. To conclude, for the first time, we demonstrate the importance of the IL-22 autocrine pathway in a lymphoid malignancy, and reveal yet another novel function of NPM-ALK.