There is evidence that crescentic glomerulonephritis initiated in rodents by heterologous antibodies against the glomerular basement membrane (anti–GBM glomerulonephritis) depends on a Th1–type immune reaction. Interleukin 12 (IL–12) is crucial for the development of Th1 helper cells, and interferon gamma (IFN–γ) is a major proinflammatory product of these cells. In order to test the role of the two cytokines in anti–GBM glomerulonephritis we used mice lacking either the p40 chain of IL–12 (IL–12–/–) or the IFN–γ receptor (IFN–γR–/–). Glomerulonephritis was induced by injecting a rabbit anti–GBM serum in mice preimmunized against rabbit IgG. Glomerulonephritis was assessed on the basis of proteinuria, immunofluorescence findings and histology. IL–12–/– mice were completely protected against glomerulonephritis. In contrast, IFN–γR–/– mice were more severely affected than wild–type mice. Similarly, cutaneous delayed–type hypersensitivity, a typical Th1 response, was abolished in the IL–12–/–, mice but increased in the IFN–γR–/– mice. The data obtained in IL–12–/– mice support the view that crescentic glomerulonephritis in this model represents a Th1 response. Since IFN–γ is not required, other products of Th1 cells are likely to mediate glomerulonephritis.