The present study examined the temporal expression of nitric oxide synthase (iNOS) and cyclo-oxygenase (COX)-2 in rat brains after traumatic brain injury (TBI). We studied the effects of mercaptoethylguanidine (MEG), a dual inhibitor of the inducible iNOS and COX with scavenging effect on peroxynitrite, on physiologic variables, brain pathogenesis, and neurologic performance in rats after a lateral fluid percussive-induced TBI. Mean arterial blood pressure and percentage cerebral tissue perfusion in MEG-treated TBI rats showed significant improvement when compared with TBI rats. Immunohistochemical analysis showed a marked number of iNOS and COX-2 immunopositive cells in the cerebral cortex ipsilateral to the injury in TBI rats when compared with MEG-treated TBI rats. MEG also significantly decreased the number of hyperchromatic and shrunken cortical neurons when compared with TBI rats' brain nitrate/nitrite, and prostaglandin E2 levels were attenuated in MEG-treated TBI rats when compared with TBI rats. It is therefore suggested that treatment of MEG via inhibition of iNOS and COX-2 might contribute to improved physiologic variables, neuronal cell survival, and neurologic outcome after TBI.