OBJECTIVE Prescription dose naproxen has been reported to have an antiplatelet effect similar to low-dose aspirin (ASA). This study evaluated the platelet inhibitory effects of over-the-counter (OTC) doses of naproxen sodium (NAPSO) compared to that of a prescription dose of NAPSO and to low-dose enteric-coated aspirin (EC-ASA). METHODS This was a phase I, open-label, randomized, placebo-controlled, two-way crossover, multi-dose, pharmacodynamic trial conducted in healthy male and female volunteers (n = 48, mean age = 41.7 years). All subjects received 7 days of either prescription dose NAPSO (550 mg twice daily), OTC doses of NAPSO (220 mg two or three times daily), or placebo twice daily (period 1). After a minimum 6-day washout period, all subjects then received 7 days of EC-ASA 81 mg once daily (period 2). All study medications were taken by mouth. METHODS Inhibition of serum thromboxane B(2) (TXB(2)), as a marker of platelet cyclooxygenase-1 (COX-1) inhibition, measured 24 h after the day 7 morning dose. This was measured after both period 1 and period 2. RESULTS After 7 days of treatment in period 1, mean inhibition of TXB(2) was 47% for placebo and > or =98% for all doses of NAPSO. After 7 days of EC-ASA 81 mg, mean inhibition of TXB(2) was > or = 97% (period 2). CONCLUSIONS Out-patient study setting. CONCLUSIONS These data suggest that OTC doses of NAPSO (220 mg two or three times daily) have an antiplatelet effect similar to EC-ASA 81 mg and to prescription dose NAPSO (550 mg twice daily).