BACKGROUND It is not known whether smoking increases the risk of end-stage renal failure (ESRF) in patients with primary renal disease. METHODS We performed a retrospective multicenter case-control study including 582 patients from nine centers in Germany, Italy and Austria. The diseases investigated were IgA glomerulonephritis (IgA-GN) as a model of inflammatory renal disease and autosomal dominant polycystic kidney disease (ADPKD) as a model of non-inflammatory renal disease. Cases were patients who had progressed to ESRF and controls were patients who were not in ESRF, that is, whose serum-creatinine failed to progress to >3 mg/dl during the observation period and who did not require renal replacement therapy. Matching for renal disease (IgA-GN, ADPKD), gender, age at renal death and region of residence resulted in 102 individually matched pairs (IgA-GN N = 54, ADPKD N = 48). Multiple conditional logistic regression was used to estimate adjusted odds ratios for independent tobacco effects. RESULTS In men (matched pairs: IgA-GN N = 44, ADPKD N = 28), a significant dose-dependent increase of the risk to progress to ESRF was found (non-adjusted). The baseline risk was defined as <5 pack-years (PY): (i) 5 to 15 PY, odds ratio 3.5 (95% CI 1.3 to 9.6), P = 0.017; (ii) >15 PY = 5.8 (2.0 to 17), P = 0.001. Systolic blood pressure, ACE inhibitor treatment and age at diagnosis emerged as potential confounders. After adjustment, the risk for ESRF in men with >5 PY was highly increased for patients without ACE inhibitor treatment [10.1 (2.3 to 45), P = 0.002] but not with ACE inhibitor treatment [1.4 (0.3 to 7.1), P = 0.65]. CONCLUSIONS Smoking increases the risk of ESRF in men with inflammatory and non-inflammatory renal disease.