Increasing evidence suggests that heat shock factor 1 exerts endogenous protective effects on working memory under conditions of chronic psychological stress. However, the precise underlying mechanisms remain poorly understood. This study examined the protective factors affecting working memory in heat shock transcription factor 1 gene knockout mice. The results indicated that the number of correct T maze altations decreased following mild chronic psychological stress in knockout mice. This change was accompanied by a decrease in neurogenesis and an increase in neuronal apoptosis in the hippocampal dentate gyrus. The number of correct T maze altations was positively correlated with neurogenesis in hippocampal dentate gyrus, and negatively correlated with neuronal apoptosis. In wild type mice, no significant difference was detected in the number of correct T maze altations or neuronal apoptosis in hippocampal dentate gyrus. These results indicate that the heat shock factor 1 gene has an endogenous protective role in working memory during mild chronic psychological stress associated with dentate gyrus neuronal apoptosis.Moreover, dentate gyrus neurogenesis appears to participate in the protective mechanism.