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INTRODUCTION: Intraabdominal adhesions are a major source of morbidity and efforts to prevent them remain limited. Our laboratory has previously shown that adhesions are reduced by mechanisms that upregulate peritoneal fibrinolysis and antioxidant capacity. NAC is a clinically relevant antioxidant whose ability to reduce adhesions is unknown. We hypothesized that NAC would reduce adhesions and characterized its effects on peritoneal fibrinolysis and antioxidant defenses. We furthermore studied its effect on normal wound healing and tested its efficacy when given orally. METHODS: Male Wistar rats were randomized to three groups: NON-OP (n=8), OP+Saline (n=30) or OP+NAC (n=30). Operated animals were administered either 1-mL normal saline (vehicle) or NAC (150mg/kg) IP BID on pre-op day 1, operative day and post-op day 1. On operative day, abdominal adhesions were induced using our ischemic button model. Animals were sacrificed at 7 days for adhesion scoring or at 24hrs to evaluate peritoneal fluid and tissue for fibrinolytic activity, tPA and PAI-1 mRNA by RT-PCR and protein by EIA and Western blot, glutathione (GSH) and 8-isoprostane by EIA. In a second experiment, animals (n=8) received a colonic anastomosis on operative day while undergoing the same 3-day BID dosing regime of IP saline or NAC. The anastomosis underwent bursting pressure measurement on post-operative day 7. In the final experiment, animals (n=12) received the adhesion operation and a 3-day BID dosing regime of oral saline or NAC (1200mg/kg) and were scored on post-operative day 7.RESULTS: NAC reduced adhesions by 53% (36 ± 5% vs. 77 ± 5%, p<0.001) and increased peritoneal fibrinolytic activity over two-fold (795 ± 167% vs. 350 ± 11% of NON-OP, p=0.002). Peritoneal tissue tPA mRNA levels increased by two-fold with NAC (p=0.007) while PAI-1 protein levels decreased by 30% (p=0.047). The tPA/PAI-1 protein ratio in the peritoneal fluid increased by 69% with NAC (158 ± 24.5 vs. 93.4 ± 11.8, p=0.039). Surgery reduced peritoneal GSH levels by 92% but NAC did not reconstitute GSH levels. NAC decreased 8-IP, however, by 46% (11.8 ± 5.3 vs. 21.7 ± 11.9 pg/mg protein, p=0.009) compared to OP+Saline. Colonic anastomotic healing was not affected by IP NAC treatment (356 ± 57 vs. 299 ± 49 mmHg). Oral NAC did not reduce adhesion formation (78 ± 8% vs. 69 ± 9%).CONCLUSIONS: NAC administered intraperitoneally, but not orally, reduces adhesion formation while upregulating peritoneal fibrinolytic activity and antioxidant defenses without affecting normal wound healing. These data suggest a potential new therapeutic use for NAC in adhesion prevention.