The effect of 7 consecutive days dosing with anti-inflammatory drugs on rat gastric mucosal PGE2 and 6-keto-PGF1 alpha concentrations were studied. Normal adult rats were given daily, single oral doses of etodolac (3 or 8 mg/kg/day), naproxen (3 mg/kg/day), or aspirin (300 mg/kg/day). Two hours after administration of the last dose, the animals were killed and the gastric mucosal PGE2 and 6-keto-PGF1 alpha were extracted and measured by radioimmunoassay. At equieffective anti-inflammatory doses in the rat, etodolac (3 mg/kg/day) did not significantly lower the concentrations of either PGE2 or 6-keto-PGF1 alpha, whereas both 3 mg/kg/day of naproxen and 300 mg/kg/day of aspirin significantly lowered the concentrations of both prostaglandins. The effects of naproxen and aspirin on the 6-keto-PGF1 alpha concentrations were also significantly different from that of etodolac at 3 mg/kg/day. At a higher dose of 8 mg/kg/day, etodolac did significantly lower the concentrations of PGE2 (by 33%) but not of 6-keto-PGF1 alpha. Our present data thus supports the hypothesis that the relatively weak inhibiting effect of etodolac on the gastric mucosal prostaglandin concentrations may contribute to its excellent GI profile observed in man.