In 5 animal spp., the only quantitatively significant biotransformations undergone by cis-5-fluoro-2-methyl-1-[p-(methylsulfinyl) benzylidene]indene-3-acetic acid (sulindac) are oxidation of its sulfinyl substitutent to sulfone, and reduction to sulfide. The former metabolite is eliminated unchanged and elicits no pharmacological response. The sulfide is readily reoxidized in vivo to sulindac. In each of 7 in vivo models of inflammation, sulfide administered as such is more active than sulindac. The inference that the activity of sulindac might be attributed in whole or in part to the sulfide was tested directly by comparison of responses with concentrations of each reduction oxidation species in appropriate biological fluids. Regression analyses of circulating levels of sulindac and sulfide vs. inhibition of rat paw edema, and of their levels in synovial fluid vs. response in the dog knee joint assay, show highly significant correlations only for sulfide. Sulindac thus appears to be a latentiated or pro-drug, oral dosage with which may circumvent the gastrointestinal side effects commonly associated with nonsteroid anti-inflammatory agents.