Background: Smoking increases the risk of developing renal cell carcinoma (RCC). The prognosis of active smokers compared with non-smokers with metastatic RCC (mRCC) has not been well characterized. Methods: Smoking data from 1,842 patients with mRCC treated with targeted therapy were collected through the International mRCC Database Consortium (IMDC) from 8 Cancer Centers. Patients were categorized as current, former and non-smokers at the time of starting targeted therapy, and analyzed for differences in IMDC risk criteria, response rate (RR), progression- free-, (PFS) and overall survival (OS). Results: Overall, 292 (15.9%), 755 (41.0%), and 795 (43.1%) were current, former, and non-smokers. There were no differences in sarcomatoid features, number of metastatic sites or non-clear cell histology in either former or current smokers when compared with non-smokers. Likewise, former smokers had statistically similar IMDC risk groups compared to non-smokers. However, current smokers were more likely to have hypercalcemia (p=0.004), neutrophilia (p=0.038), thrombophilia (p=0.002), and more patients had higher numbers of IMDC risk features (p=0.014) when compared with non-smokers. The RR at first-line targeted therapy of former (p=0.89) and current smokers (p=0.13) were similar to non-smokers. No differences in PFS were noted: 7.7 vs. 7.6 vs. 6.2 months (mo) in non-, former (p=0.92), and current smokers (p=0.66). Interestingly, while former- and non-smokers had comparable OS times (23.7 vs. 23.1 mo; p=0.71), current smokers had significantly shorter OS (15.8 mo; p=0.001) than non-smokers. Current but not former smoking status was an independent poor prognosis factor (HR=1.28; p=0.006) when adjusted for the IMDC risk criteria. Moreover, each pack year increased the risk of death 1% (HR=1.01; p=0.039). Conclusions: Active smoking is associated with more advanced IMDC risk criteria and diminished OS in mRCC patients treated with targeted therapy agents. On the other hand, patients who quit smoking returned to a similar risk of death compared to patients who never smoked. Smoking cessation should be a counselling priority among mRCC patients receiving targeted agents.