ABSTRACT The tumor suppressor proteins IRF‐1 and p53 are involved in response pathways after DNA damage. In different cell types, IRF‐1 and p53 can cooperate to produce cell cycle arrest (embryo fibroblasts) or can independently trigger apoptosis (lymphoid cells). p53 may also regulate DNA repair, but there is no information on IRF‐1 and repair. The cell lineage dependency of these effects precludes extrapolation of findings to other tissues of relevance to human cancer. Here, we report the consequences of IRF‐1 deficiency for apoptosis, cell cycle arrest, and DNA repair in primary hepatocytes after DNA damage and extend previous work on the role of p53 in hepatocytes. IRF‐1‐deficient hepatocytes showed reduced DNA repair activity compared with wild‐type, as assessed by unscheduled DNA synthesis after UV irradiation (10J/m 2 ) and by host reactivation of a UV‐damaged reporter construct. p53‐deficient hepatocytes also showed reduced unscheduled DNA synthesis after UV, but there was no impairment of specific repair in host reactivation assays. IRF‐1 deficiency did not affect the p53‐dependent G 1 /S arrest after UV irradiation. Hepatocyte apoptosis after UV treatment, previously reported to be independent of p53, was also independent of IRF‐1. However, IRF‐1 deficiency produced dysregulation of p53, manifested as increased transactivation of a p53‐reporter plasmid in undamaged hepatocytes, and accelerated p53 stabilization after DNA damage. Hence, in hepatocytes, IRF‐1 is not required for growth arrest or apoptosis after DNA damage, but the results suggest for the first time a role in DNA repair regulation.—Prost, S., Bellamy, C. O. C., Cunningham, D. S., Harrison, D. J. Altered DNA repair and dysregulation of p53 in IRF‐1 null hepatocytes. FASEB J. 12, 181–188 (1998)