Pancreatic beta cell damage caused by proinflammatory cytokines interleukin-1beta (IL-1beta), interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha) is a key event in the pathogenesis of type 1 diabetes. The suppressor of cytokine signaling-1 (SOCS-1) blocks IFNgamma-induced signaling and prevents diabetes in the non-obese diabetic mouse. Here, we investigated if SOCS-1 overexpression in primary beta cells provides protection from cytokine-induced islet cell dysfunction and death. We demonstrate that SOCS-1 does not prevent increase in NO production and decrease in glucose-stimulated insulin secretion in the presence of IL-1beta, IFNgamma, TNFalpha. However, it decreases the activation of caspase-3, -8 and -9, and thereby, promotes a robust protection from cytokine-induced beta cell death. Our data suggest that SOCS-1 overexpression may not be sufficient in preventing all the biological activities of IFNgamma in beta cells. In summary, we show that interference with IFNgamma signal transduction pathways by SOCS-1 inhibits cytokine-stimulated pancreatic beta cell death.