Cells from patients with ataxia telangiectasia (AT) are hypersensitive to ionizing radiation and are defective in the regulation of DNA synthesis. A complementary DNA that corrects the radiation sensitivity and DNA synthesis defects in fibroblasts from an AT group D patient was isolated by expression cloning and shown to encode a truncated form of IκB-α, an inhibitor of the nuclear factor kappa B (NF-κB) transcriptional activator. The parental AT fibroblasts expressed large amounts of the IκB-α transcript and showed constitutive activation of NF-κB. The AT fibroblasts transfected with the truncated IκB-α expressed normal amounts of the IκB-α transcript and showed regulated activation of NF-κB. These results suggest that aberrant regulation of NF-κB and IκB-α contribute to the cellular defect in AT.