Caffeine has been found to potentiate the acute anti-inflammatory activity of aspirin, indomethacin, and phenylbutazone, but not the activity of sodium salicylate or hydrocortisone, in the carrageenan pleurisy or hindlimb models of inflammation in the rat. The mobilization of inflammatory cells was not affected by aspirin in the presence or absence of caffeine. The mild analgesia produced by aspirin was confined to a hyperalgesic test in which this drug was able to reduce inflammation and concomitant hyperalgesia and thereby produce an "apparent" analgesic effect. This "apparent" analgesia produced by aspirin was potentiated by caffeine. The mechanism responsible for the potentiated anti-inflammatory and mild analgesic activity of aspirin remains unknown since caffeine did not alter the plasma salicylate levels or prostaglandin synthetase inhibition produced by aspirin.