Probenecid induced major alterations in the half‐life. renal clearance, and metabolism of naproxen. In 6 healthy subjects who received 500‐mg single oral doses of naproxen alone and (following two days of probenecid loading) with 500 mg of probenecid 4 times a day, there was an increase in naproxen plasma half‐life from the normal 14 to 37 hr. Twenty‐four hour naproxen plasma levels were doubled by probenecid. but the rate and extent of absorption were not affected. In an 8‐day chronic administration experiment (250 mg twice daily). naproxen steady‐state plasma levels measured before the morning dose were increased 50% by coadministration of 500 mg probenecid twice daily. The major probenecid effects on naproxen metabolism were a 66% reduction of the naproxen conjugates excreted in the urine and an increase in urinary 6‐0‐desmethyl naproxen. The renal clearance of unchanged naproxen was markedly depressed. We conclude that probenecid retards naproxen plasma clearance by inhibiting naproxen glucuronide formation and renal clearance of naproxen. The renal clearance effect is the result of the blocking of tubular secretion of organic anions by probenecid. Inhibition of conjugate formation by probenecid may be the result of successful competition for conjugative processes since a large percentage of both drugs are cleared from the plasma by conjugation. Because of this interaction, patients who receive naproxen and probenecid in combination will have higher steady‐state plasma levels of naproxen and form more of the 6‐0‐desmethyl metabolite than when probenecid is not used.