In ischemic stroke, vascular occlusion rapidly induces tissue infarct. Over the ensuing hours, damage spreads to adjacent tissue and forms transition zone (penumbra), which is potentially salvageable. Epigenetic regulation of chromatin structure controls gene expression and protein synthesis. We studied the expression of histone deacetylases HDAC1 and HDAC2 in the penumbra at 4 or 24 h after photothrombotic stroke (PTS) in the rat brain cortex. PTS increased the expression of HDAC1 and HDAC2 in penumbra and caused the redistribution of HDAC1 but not HDAC2 from the neuronal nuclei to cytoplasm. In astrocytes, HDAC1 expression and localization did not change. In neurons, HDAC2 localized exclusively in nuclei, but in astrocytes, it was also observed in processes. PTS induced neuronal apoptosis in the penumbra. TUNEL-stained apoptotic neurons co-localized with HDAC2 but not HDAC1. These data suggest that HDAC2 may represent the potential target for anti-stroke therapy and its selective inhibition may be a promising strategy for the protection of the penumbra tissue after ischemic stroke.