The nephrotoxic potentials of a high-osmolar contrast medium, diatrizoate, and of a low-osmolar contrast medium, ioxaglate, were compared during early degenerative gentamicin-induced nephropathy in the rat. Male rats (13-22/group) were uninephrectomized. Six days later, the aorta was clamped above the renal artery, and either diatrizoate or ioxaglate was administered (1 ml/min for 3 min) via an aortic puncture into the remaining kidney. Some of the rats received chronic treatment with gentamicin (50 mg/kg/day i.m., 4 days), starting 2 days before and ending 1 day after contrast medium administration. Two control groups, only one of which received gentamicin, were subjected to a 3-min renal ischemia. The creatinine clearance (CrCl) per 100 g body weight was determined before and 24 and 48 h after contrast medium injection. A second study (6 rats/group) evaluated urinary N-acetyl-β-D -glucosaminidase (NAG) excretion and the histologic appearance of the kidneys (blinded analysis) in the same experimental groups. Gentamicin induced a significant decrease in CrCl at baseline(0.35 ± 0.19vs.0.41 ± 0.19 ml/min; p < 0.01) and an increase in urinary NAG(128 ± 92 vs. 39 ± 57 µmol/h/mmol creatinine; p < 0.01). Taking into account these differences at baseline, univariate repeated-measures analysis showed that on day 1 diatrizoate caused a more marked decrease in CrCl than ioxaglate (p < 0.05), whether or not gentamicin was also administered. On day 2, the depressant effect of diatrizoate associated with gentamicin persisted (CrCl vs. day 0 = -0.19 ± 0.10 ml/min), while that of diatrizoate alone returned to baseline (-0.05 ± 0.24 ml/min). Conversely, the effects of ioxaglate did not differ from those of the control groups at the two measuring times. Although the effects of contrast medium-gentamicin interaction were not significant for urinary NAG, the gentamicin plus diatrizoate combination suggested greater toxic potential than the gentamicin plus ioxaglate combination on day 2 (NAG vs. day 0 = +260 ± 528 vs. +22 ± 119 µmol/h/mmol creatinine). In contrast to ioxaglate alone, which only induced vacuolization, diatrizoate alone provoked foci of tubular necrosis associated with vascular lesions. Gentamicin alone induced irregular vacuolization. Contrary to the findings for gentamicin plus diatrizoate, no necrotic foci were observed with gentamicin plus ioxaglate. The nephrotoxic potential of diatrizoate after intra-renal administration is greater than that of ioxaglate administered in the rat during the early degenerative phase of gentamicin-induced nephropathy.