The mild analgesic activities of aspirin, phenacetin and acetaminophen have been compared in the trypsin, kaolin and carrageenan hyperalgesic assays as well as in the acetic acid writhing test. The trypsin and kaolin hyperalgesic assays were designed to be unaffected by drugs with anti-inflammatory activity. Aspirin and acetaminophen were inactive in these two tests at dose levels devoid of side effects. Phenacetin was active in the trypsin and kaolin assays with oral ED50's of 114 +/- 36.2 and 107 +/- 11.5 mg/kg, respectively. Non-steroidal anti-inflammatory drugs as well as phenacetin and acetaminophen were active in the acetic acid writhing and carrageenan hyperalgesic assays. This led to evaluation of phenacetin and acetaminophen as anti-inflammatory agents. Both of these latter drugs were active in the carrageenan pleurisy and adjuvant arthritis models of inflammation. In all studies phenacetin was equipotent to or more potent than acetaminophen. The data suggest that the analgesia produced by aspirin and acetaminophen results from their anti-inflammatory activity whereas the analgesia produced by phenacetin has two components, one dependent on and one independent of anti-inflammatory activity.