The interleukin-12 receptor β2 (Il12rb2) gene is silenced in tumor cells from different human B-cell malignancies as opposed to their normal counterparts. It was hypothesized that this silencing allows neoplastic B cells to escape the control exerted by IL-12 on their growth. The aim of this study was to investigate whether targeted inactivation of the Il12rb2 gene in mice resulted into increased susceptibility to spontaneous tumor formation and immunopathology. Il12rb2 gene–deficient animals developed in the first year of life immune-complex mesangial glomerulonephritis with serum antinuclear antibodies. In older animals, multiorgan lymphoid infiltrates with features of vasculitis and Sjögren syndrome were detected in association with systemic B- and T-cell activation. In half of aged animals, lymph node plasmacytoma or lung carcinoma was observed. A mechanism for spontaneous development of autoimmune pathology and B-cell tumors is suggested by a strong IL-6 up-regulation detected in splenocytes and lymphoid infiltrates associated with oligoclonal B-cell expansion. The emergence of lung tumors may likely be attributed to an interferon-γ (IFN-γ) deficiency secondary to lack of IL-12 signaling. The development of autoimmunity, lymphoproliferation, and B-cell tumors in Il12rb2 knockout (KO) mice suggests that IL-12 functions physiologically to restrain aberrant B-cell activation.