The purpose of this study was to compare the nephrotoxic potential of amikacin (AK) and gentamicin (GM) in patients (pts) with normal renal function at the beginning of the treatment (Tx) in an open comparative and prospective trial. Nephrotoxicity (NFTX) was defined as a blood creatinine (Cr) increase of at least 50% from the basal (normal) level, or an increase to higher than normal level during, at the end or after Tx. Peak and trough blood GM and AK levels were determined at 72 h of Tx to make proper adjustments in dosing. The two groups (GM, n = 27 and AK, n = 38) were similar in population composition, underlying pathology and infectious process requiring antimicrobials. Patients in the GM group tended to be older (mean age, 56 years) than the AK (mean age, 48 years) p NS; the latter had received more frequently aminoglycoside Tx (69 vs 11%) p less than 0.0005. The GM group received a comparatively lower dose than the AK (x = 2.87 mg/k/d and 16 mg/k/d respectively) but duration of Tx was similar. Fifteen of 27 pts receiving GM (56%) and 7 of 38 receiving AK (18.2%) developed NFTX, p less than 0.004. Five pts in the GM group (18.5%) and 2 in the AK (5.2%) had clinical NFTX. The difference in NFTX persisted after age adjustment. There were no intra or inter group significant differences between pts with or without NFTX. In conclusion, in pts with initial normal renal function gentamicin was significantly more nephrotoxic than amikacin.