OBJECTIVE—To determine the risk factors for adverse renal outcome in type 2 diabetic patients who underwent renal biopsy and were followed-up longitudinally. RESEARCH DESIGN AND METHODS—We examined 68 consecutive patients with type 2 diabetes during the period of 1985–1999 who underwent renal biopsy for proteinuria ≥1 g/day, renal involvement (proteinuria or renal impairment) at the absence of retinopathy, renal involvement with duration of diabetes <5 years, or unexplained hematuria of glomerular origin. Their clinical features and underlying renal lesion were correlated with the renal outcome after longitudinal follow-up. Three groups of patients were defined based on their renal pathology: group I consisted of 24 patients (35%) with diabetic glomerulosclerosis (DGS) alone, group II consisted of 13 patients (19%) with nondiabetic nephropathy (NDN) superimposed on DGS, and group III consisted of 31 patients (46%) with NDN alone without evidence of DGS. RESULTS—After a mean follow-up of 123 months from the diagnosis of type 2 diabetes (74 months from the time of renal biopsy), univariate analysis showed that risk factors for reaching end-stage renal disease (requiring maintenance dialysis, or a serum creatinine [SCr] ≥700 μmol/l) included proteinuria ≥2 g/day (P = 0.0087), SCr >120 μmol/l (P = 0.0005), presence of retinopathy (P < 0.00001) at the time of biopsy, and biopsy showing DGS (groups I and II) (P = 0.035). On multivariate analysis, retinopathy was the only independent variable correlated with end-stage renal failure. This study also showed that the association of hematuria or proteinuria with the absence of retinopathy constitutes the strongest indication for a nondiabetic lesion (positive predictive values of 94%). CONCLUSIONS—Patients with type 2 diabetes undergoing renal biopsy constitute a heterogeneous group by their clinical presentations and underlying pathology, but longitudinal studies on the renal outcome of these patients remain limited. Our study showed that renal biopsy is indicated in selective diabetic patients because of potentially treatable nephropathy and of a better prognosis than DGS.