Clinical studies suggest that smoking is a risk factor in the progression of chronic kidney disease, including diabetic nephropathy. The mechanisms involved are not completely understood. We have previously demonstrated that nicotine, one of the compounds present in large amounts in tobacco, promotes mesangial cell proliferation and fibronectin production. In this study, we hypothesized that exposure to environmental tobacco smoke (ETS) promotes the progression of diabetic nephropathy by increasing the expression of pro-fibrotic cytokines such as TGF-β and the extracellular matrix proteins fibronectin and collagen IV. Six-week-old diabetic (db/db) mice were divided into two groups. The experimental group (n=12) was exposed to ETS at a concentration of 30 mg/m 3 for 6 hrs/day, 5 days/week for eight weeks. The control group (n=8) was exposed to room air. Urine was collected before euthanasia for albumin (ELISA), and creatinine measurements (mass spectrometry). After euthanasia, the kidneys were harvested for morphometric analysis and Western blot analysis. Serum was saved for cotinine measurements by ELISA. ETS exposure resulted in serum levels of cotinine similar to those found in human smokers. ETS exposure for eight weeks induced significant mesangial expansion (~ 50% increase) that was accompanied by concomitant increases in TGF-β and fibronectin expression (~20 %). ETS however, did not modify results in significant changes in urinary albumin excretion. These studies demonstrate that ETS exposure worsens the progression of diabetic nephropathy by increasing the amount of mesangial expansion and that these effects are likely mediated by increased expression of pro-fibrotic cytokines such as TGF-β.