Background: Eukaryotic Initiation Factor 4E (eIF4E) is pivotal in translating mRNAs with complex 5′ un-translated regions (UTRs). A target-specific gene therapy was developed by splicing a complex 5′UTR upstream of the herpes simplex virus thymidine kinase (TK) gene in an adenovirus vector (Ad-HSV-UTK). Translation of the suicide TK gene is restricted to cells that overexpress eIF4E. We investigated the efficacy of this novel therapy in a rat peritoneal carcinomatosis (PC) model. Methods: A PC model was developed by implanting a syngeneic 0.25 cm3 tumor into Fisher 344 rats' omentum. Rats were grouped as follow: No surgery (Ø CS), cytoreductive surgery alone (CS), and CS + Ad-HSV-UTK + gancyclovir (GCV). 109 Ad-HSV-UTK was injected intraperitoneally (i.p.) and GCV (50 mg/kg) was administered i.p. every other day, beginning on postoperative day 2. The Kaplan-Meier survival method and log-rank test were statistical tests used. Results: Treated rats had a significantly longer median and overall survival than the Ø CS and CS groups (P = .012). The median survivals for the treated rats, Ø CS, CS were 18 days, 9 days, and 11 days, respectively. Conclusions: Treatment with a novel suicide gene therapy following cytoreductive surgery prolonged survival in a rat peritoneal carcinomatosis model.