Naproxen is an anti-inflammatory drug used in a variety of anti-inflammatory syndromes. There is evidence showing that tizanidine enhances the anti-inflammatory effect in rats. This study examines the pharmacokinetics of naproxen when it is combined with tizanidine. Combining these two drugs is an attractive modality for inflammation complaints. Oral coadministration of naproxen/tizanidine produced a synergistic anti-inflammatory effect in rats. The swelling of the rat paw was measured by a plethysmometer using carrageenan as an inflammatory agent. In this study, rats received oral doses of naproxen (1, 3, and 4.2 mg/kg), and these doses were combined with a fixed dose of tizanidine (0.01 mg/kg). To evaluate the pharmacokinetic interaction between naproxen/tizanidine, blood samples were obtained at selected times in the 24 h after oral administration and were analyzed using a validated high-performance liquid chromatography method. Systemic administration of naproxen alone or in combination with tizanidine produced a dose-dependent anti-inflammatory effect. In the pharmacokinetic interaction study, no statistically significant difference was observed for the naproxen concentration-time profiles in the presence of tizanidine. The experimental findings suggest that systemic tizanidine is able to increase the naproxen-induced anti-inflammatory effect in rats. This effect was not due to a modification of the bioavailability of naproxen.