Prospective studies have established smoking as an independent risk factor for diabetic nephropathy, suggesting an adverse effect of smoking on glomerular structure and function. To test this hypothesis, this study evaluated GFR, metabolic profile, and smoking habits in 96 patients with type 2 diabetes and abnormal albumin excretion rate (AER). All patients underwent percutaneous kidney biopsy: mesangial fractional volume [Vv (mes/glom)] and glomerular basement membrane (GBM) width were estimated by electron microscopic morphometric analysis; interstitial fibrosis was estimated semiquantitatively by light microscopy. Forty-eight patients were smokers. Compared with nonsmokers, smokers had higher values of HbA(1c) (P = 0.002), AER (P = 0.026), GFR (P = 0.004), and GBM width (P = 0.002); moreover, GFR was higher in current smokers than in former smokers (P = 0.001), and GBM width was related to heavy smoking (F = 5.4; P = 0.006). Multiple linear regression analyses revealed that HbA(1c) was associated with fasting blood glucose (beta coef = 0.52; P < 0.001), smoking habit (beta coef = 0.31; P < 0.001), insulin therapy (beta coef = 0.22; P = 0.012), and male gender (beta coef = -0.20; P = 0.020); AER was related to Vv (mes/glom) (beta coef = 0.32; P = 0.003), GBM width (beta coef = 0.28; P = 0.016), and interaction between smoking habit and HbA(1c) (beta coef = 0.24; P = 0.040). GFR was negatively correlated with Vv (mes/glom) (beta coef = -0.57; P < 0.001) and age (beta coef = -0.29; P = 0.001) and positively correlated with GBM width (beta coef = 0.27; P = 0.012), heavy current smoking (beta coef = 0.24; P = 0.028), and HbA(1c) (beta coef = 0.28; P = 0.040); GBM width was explained by Vv (mes/glom) (beta coef = 0.53; P < 0.001), interaction between heavy smoking and HbA(1c) levels (beta coef = 0.25; P = 0.003), and diabetes duration (beta coef = 0.23; P = 0.010). Smoking habit did not affect the index of interstitial fibrosis. In conclusion, cigarette smoking affects glomerular structure and function in type 2 diabetes and may be an important factor for the onset and progression of diabetic nephropathy.