We have previously reported that radiocontrast agents induce direct renal tubule cell toxicity in vitro. The observed toxic effects were markedly potentiated by concomitant hypoxia. In addition, we have reported that the ionic radiocontrast agent diatrizoic acid is more toxic than the nonionic radiocontrast agent iopamidol in this system. Using suspensions enriched in rabbit renal proximal tubule segments, we compared the direct toxicities of the ionic dimeric ioxaglic acid to the nonionic monomeric compound iopamidol. Toxicity was assessed by comparing tubule potassium and calcium content, ATP levels, and respiratory rates after exposure to clinically achievable concentrations of radiocontrast agents. Ioxaglate (25 mM) produced significant declines in tubule cation content and respiratory rate with 30 min of hypoxia followed by 60 min of reoxygenation compared to molar-equivalent concentrations of iopamidol under similar conditions. Meglumine, a cationic compound frequently present in ionic contrast agent solutions, and ioxaglate tubule toxicity was additive. Iopamidol and ioxaglate exhibited similar tubule cell toxicity when comparison was based on iodine content. These experimental results suggest that the intrinsic nephrotoxic potential of ioxaglic acid is greater than that of iopamidol on a molar basis, but that the nephrotoxic potential of the two radiocontrast agents is similar when comparison is based upon iodine content.