Interferon‐gamma (IFN‐γ) is a pleiotropic cytokine that is critically involved in the pathogenesis of inflammatory demyelinating diseases. There is strong evidence that IFN‐γ can function as a distinct and independent injurious factor to oligodendrocyte progenitor cells (OPCs). The intracellular signaling pathways leading to OPC death, however, remain poorly understood. In this study, we examined IFN‐γ signaling in OPCs in relation to cell death in vitro. Using expression knock‐down and forced overexpression methods, we directly demonstrated the role of signal transducer and transcription activator 1 (STAT1) and interferon‐regulated factor 1 (IRF‐1) in IFN‐γ‐ induced OPC death. In addition, our study identified two proapoptotic genes, caspase 1 and double‐stranded RNA‐dependent protein kinase (PKR), whose expression was upregulated by IFN‐γ and transcriptionally controlled by IRF‐1. The conclusion of this study is that STAT1 and IRF‐1 function as components of the signaling pathway that mediates IFN‐γ‐induced OPC death. © 2009 Wiley‐Liss, Inc.