The aim of this study was to compare the nephrotoxic potential of amikacin (AK) and gentamicin (GM) in patients with normal baseline renal function. This study was a 1-year, non-interventional prospective study of patients administered either GM or AK. The study was carried out at the internal medicine department of Al-Watani governmental study. Nephrotoxicity was defined as a serum creatinine (SCr) increase of >or=0.5 mg/dL from the basal (normal) SCr level. The two groups (GM, n = 45 and AK, n = 49) were similar in population composition, and underlying pathological and infectious processes requiring antimicrobials. No significant difference in age was found between patients in the GM and AK groups, P = 0.83. Patients in the GM group received comparatively lower doses than those in the AK group (mean = 2.5 mg/kg/day and 14.4 mg/kg/day, respectively) but the duration of treatment was similar. Sixteen of 45 patients receiving GM (35.6%) and eight of 49 patients receiving AK (16.3%) developed nephrotoxicity, P = 0.033. Single daily dosing with GM, regardless of the total daily dose, produced less nephrotoxicity than multiple dosing. In contrast, AK given at a total dose of 1 g daily, showed no benefit of single dosing compared with multiple dosing. In patients with initial normal renal function, GM was significantly more nephrotoxic than AK. Multiple dosing of GM was more nephrotoxic than single dosing. AK-induced nephrotoxicity was not significantly dependent on dosing frequency.