Cigarette smoking causes cardiovascular disease and is associated with poor kidney function in individuals with diabetes mellitus and primary kidney diseases. However, the association of smoking on patients with atherosclerotic renal artery stenosis has not been studied. The current study utilized data from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL, NCT00081731) clinical trial to evaluate the effects of smoking on the risk of cardio-renal events and kidney function in this population. Baseline data showed that smokers (n = 277 out of 931) were significantly younger at enrollment than non-smokers (63.3±9.1 years vs 72.4±7.8 years; p<0.001). In addition, patients who smoke were also more likely to have bilateral renal artery stenoses and peripheral vascular disease (PVD). Longitudinal analysis showed that smokers experienced composite endpoint events (defined as first occurrence of: stroke; cardiovascular or renal death; myocardial infarction; hospitalization for congestive heart failure; permanent renal replacement; and progressive renal insufficiency defined as 30% reduction of GFR from baseline sustained for ≥ 60 days) at a substantially younger age compared to non-smokers (67.1±9.0 versus 76.1±7.9, p<0.001). Using linear regression and generalized linear modeling analysis controlled by age, sex, and ethnicity, smokers had significantly higher cystatin C levels (1.3±0.7 vs 1.2±0.9, p<0.01) whereas creatinine and estimated glomerular filtration rate (eGFR) were not different from non-smokers. From these data we conclude that smoking has a significant association with deleterious cardio-renal outcomes in patients with renovascular hypertension.