Previous studies, aimed at establishing a relationship between the inhibition of prostaglandin (PG) biosynthesis and the suppression of carrageenin-induced rat paw edema, indicated that, in a series of acetylsalicylic acid (ASA)-like compounds, there is not a good correlation between ability to inhibit platelet PG biosynthesis and anti-inflammatory activity. Some of the compounds tested had good anti-edema properties compared to ASA, but did not inhibit platelet lysate conversion of 14C-arachidonic acid (AA) to PGs. The effects of these compounds on polymorphonuclear (PMN) leukocyte accumulation in urethane-anesthetized rats were examined to extend the pharmacological profile of these agents in a search for other mechanisms of anti-inflammatory activity. 3-Methylphthalide (3-MP), an inhibitor of rat paw edema, suppressed PMN leukocyte accumulation although it is a poor inhibitor of PG cyclo-oxygenase activity. 3-Propionyloxybenzoic acid (3-PBA), an agent which increases primary platelet aggregation and arterial PGI2 production, caused increases in edema formation but decreases in PMN leukocyte accumulation. 2-Propionyloxybenzoic acid (2-PBA), which is similar to ASA in many effects, resulted in a trend towards decreased PMN leukocyte accumulation, while ASA did not. 2-Acetylbenzoic acid (ABA), an agent with anti-edema properties similar to ASA in the rat paw model but without any effect on PG biosynthesis, also caused a trend towards inhibition of PMN leukocyte accumulation. In addition to drug effects on prostaglandin biosythesis, this study indicates that drug effects on PMN leukocyte accumulation is an important determinant of anti-inflammatory potential.