Recently, the enzyme cyclooxygenase (COX) has been recognized to exist as constitutive (COX-1) and inducible isoforms (COX-2). In previous studies, drugs that were inhibitors of both COX-1 and COX-2 failed to decrease brain edema formation or improve Neurological Severity Score (NSS) after closed head trauma (CHT), although some did decrease prostaglandin-E2 (PGE2) formation. The present study examined whether or not a specific inhibitor of COX-2 (nimesulide) exerts a beneficial effect after CHT in rats. Halothane-anesthetized rats (n = 8 in each group) were randomly assigned to one of four groups: surgery, no CHT, no drug (group 1); surgery, no CHT, nimesulide 30 mg/kg intraperitoneally (IP) (group 2); surgery, CHT, no drug (group 3); and surgery, CHT, nimesulide 30 mg/kg IP (group 4). NSS was determined at 1 and 24 h, and brain tissue PGE2 concentration and water content were determined after killing at 24 h. Treatment with nimesulide did not improve NSS (NSS at 24 h = 11 ± 6 [median ± range] in group 3 and 12 ± 4 in group 4) or edema formation (brain water content at 24 h = 84.3 ± 1.8% [mean ± SD] in group 3 and 83.8 ± 1.9% in group 4). However, nimesulide did decrease cortical and hypothalamic PGE2 formation by 41% and 47%, respectively during the first hour of incubation after brain tissue sampling. The authors conclude that although nimesulide does reduce tissue PGE2 formation, it does not exert a beneficial effect on brain tissue edema or functional activity after CHT in rats.