Although the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is known to cause the impairment in mucosal defenses that are well recognized and clinically emphasized with respect to the gastrointestinal tract, less apparent is the extent of their interference with the repair of soft oral tissue. As the disturbances in nitric oxide generation and the release of endothelin-1 (ET-1) are the early signs of injury by NSAIDs, we investigated oral mucosal ulcer healing in the presence of NSAID administration by analyzing the expression of endothelin-converting enzyme-1(ECE-1), responsible for ET-1 generation, and the mucosal activity of inducible (NOS-2) and constitutive (cNOS) nitric oxide synthase responsible for nitric oxide production. Groups of rats with acetic-induced buccal mucosal ulcers were subjected twice daily for up to 10 days to intragastric administration of either indomethacin (5 mg/kg), aspirin (20 mg/kg), or the vehicle and their mucosal tissue subjected to macroacopic assessment of ulcer healing rate and biochemical measurements. While in the control group the ulcer healed by the tenth day, only a 57.2% reduction in the ulcer crater area was attained in the animals subjected to indomethacin and a 54.8% reduction in ulcer occurred in the presence of aspirin administration. Futhermore, by the tenth day, the delay in healing in the presence of indomethacin was manifested by a 4.9-fold higher rate of apoptosis, a 2.7-fold higher expression of ECE-1 activity, a 3.9-fold higher expression of NOS-2 activity and a 2.2-fold decline in cNOS activity, while the interference in ulcer healing by aspirin was characterized by a 5.6-fold higher rate of apoptosis, a 2.8-fold expressiom of ECE-1 activity, a 3.7-fold higher expression of NOS-2 activity and a 2.3-fold lower expression of cNOS activity. Our findings demonstrate that NSAIDs not only pose a well-known risk of gastrointestinal injury, but also interfere with soft oral tissue repair. The impairment in buccal mucosal ulcer healing by NSAID ingestion is manifested in up-regulation in the expression of ECE-1 responsible for ET-1 generation, suppression in cNOS, and amplification of apoptotic events that delay the healing process.