Sumatriptan is a 5HT1D agonist used in the treatment of migraine. Nonsteroidal anti-inflammatory drugs, beta-blockers, and calcium channel-blocking antagonists are used in the prophylaxis of migraine. Hence, there is a need to investigate the interaction of these prophylactic drugs with sumatriptan. The interaction of sumatriptan with propranolol, flunarizine, pizotifen, and butorphanol were reported earlier. Naproxen is shown to be effective in prophylactic treatment of migraine. In this study, the authors have investigated the circadian rhythm effect of naproxen on the pharmacokinetics of sumatriptan at 1000 and 2200 hours. Twelve healthy volunteers were treated with 100 mg sumatriptan succinate either alone or along with 500 mg naproxen orally at either 1000 or 2200 hours in a randomized Latin square design with a washout period of 10 days. Serum samples were collected at predetermined time intervals and analyzed for unchanged sumatriptan by high-performance liquid chromatography. The pharmacokinetic parameters were calculated by using model-independent methods. Naproxen had no statistically significant (p > 0.05) effect on any pharmacokinetic parameters of sumatriptan both at 1000 and 2200 hours treatment. The results of this study suggest that no alteration in the sumatriptan dosage will be necessary for migraine patients taking naproxen prophylactic therapy.