Prostaglandin E1 (PGE1) has wide-ranging effects on cytoprotection and may play a role in preventing liver failure following excessive hepatectomy. We examined the effect of PGE1 on hepatocyte apoptosis and liver regeneration after 95% hepatectomy in a rat model. PGE1 or vehicle was intravenously administered 30 minutes before and during hepatectomy. The extent of hepatocyte injury was evaluated by serum alanine aminotransferase and aspartate aminotransferase levels. To evaluate hepatocyte apoptosis and liver regeneration, terminal deoxynucleotidyl transferase dUTP nick end labeling staining and Ki67 labeling were performed. The expression levels of Bcl-xL, Bcl-2, Bax, Cyclin C, Cyclin D1, Cyclin E, p21, transforming growth factor-beta, plasminogen activator inhibitor-1, and glyceraldehyde-2-phosphate dehydrogenase mRNA were also examined by reverse transcription-polymerase chain reaction. Survival was improved in the PGE1 group (26.6%), whereas all rats in the vehicle group died within 60 hours. PGE1 significantly suppressed the release of alanine aminotransferase and aspartate aminotransferase at 12 hours postoperatively. Pretreatment with PGE1 significantly increased the Ki67-positive cell count and decreased the terminal deoxynucleotidyl transferase dUTP nick end labeling positive cell count after hepatectomy, and also significantly increased the expression levels of Bcl-xL, Cyclin C, and Cyclin D1. Our results suggest that pretreatment with PGE1 may increase survival following hepatectomy by salvaging the remaining liver tissue, which it does by inhibiting apoptosis and stimulating hepatocyte proliferation.