Inhibitors of arachidonic acid (AA) metabolism and other pharmacologic agents were evaluated against ear edema produced in mice by tetradecanoylphorbol acetate (TPA) or AA. Drugs were administered orally and topically either 30 min prior to AA or 30 min after TPA, except for steroids which were administered 2.5-3 hr prior to AA. Several cyclooxygenase (CO) inhibitors including indomethacin, aspirin, piroxicam and timegadine were without effect when administered orally against either irritant; the same drugs inhibited TPA edema when they were administered topically. Mixed CO/lipoxygenase (LO) inhibitors, phenidone and BW755C, were active orally against AA edema (ED50S of 84 and 65 mg/kg, respectively) and against TPA edema (ED50S of 235 and 88 mg/kg, respectively). Phenidone was more active topically against AA edema (ED50, 0.1 mg/ear) than BW755C (ED50, 2.8 mg/ear); however, BW755C was more active topically against TPA edema (ED50, 0.2 mg/ear) than phenidone (ED50, 0.6 mg/ear). Methylprednisolone was very effective in the AA (oral ED50, 17 mg/kg; topical ED50, greater than 1 mg/ear) and TPA models (oral ED50, 4.3 mg/kg; topical ED50, 0.03 mg/ear. MK-447 was topically and orally effective only in the TPA model. Not surprisingly, drugs were more effective topically than orally in both mouse ear edema assays. The models were somewhat selective for CO and CO/LO inhibitors; however, dapsone was orally effective in the ear models, and a number of mediator antagonists and CNS drugs, especially anti-psychotics, were topically active primarily against TPA edema. These models may be useful for the detection of in vivo activity of CO/LO or 5-LO inhibitors.