To identify candidate genes in response to ionizing radiation (IR) and discover new targets for basic research and radiation protection, whole human genome bioarrays were used to examine gene expression profiles in human lymphoblastoid AHH-1 cells exposed to IR. The results were confirmed by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). In addition, the effects of ionizing radiation on cell growth, cell cycles and apoptosis were also examined. The microarray analysis revealed a set of IR responsive genes, including 906 genes at 4 hours and 789 genes at 24 hours after exposure to 5 Gy IR. The processes of cell cycles, apoptosis, signal transduction, and DNA repair involved a high percentage of IR responsive genes, among which, caspase-4 was most strongly induced by irradiation. Consistent with this, downregulation of caspase-4 expression by antisense oligonucleotides significantly increased cell viability and protected cells from undergoing apoptosis induced by IR. Taken together, the results suggested that caspase-4 plays an important role in radiation-induced apoptosis.