The effects of Fe2+ and Cu2+ on the generation of medullary prostaglandins E2 and F2 alpha have been compared. Fe2+ markedly promoted the lipid peroxidation of rabbit kidney medulla slices. The lipid peroxidation induced by Fe2+ inhibited both prostaglandin E2 and prostaglandin F2 alpha formation to a similar extent. While Cu2+ produced only a small increase in lipid peroxidation, it had a powerful inhibitory effect on prostaglandin E2 formation. Simultaneously, prostaglandin F2 alpha production was increased. In the presence of Cu2+ the net increased amount of prostaglandin F2 alpha was much smaller than the net decreased amount of prostaglandin E2 (15-20%). These results suggest that Cu2+ has the potential to modulate prostaglandins E2 and F2 alpha synthesis by affecting endoperoxide E2 isomerase or endoperoxide reductase independent of its peroxidative action.