To study the role of smoking in renal damage, we measured gender-specific effects, dose-response relationships, and whether cessation reduced the risk of smoking on future kidney failure. During a median follow-up of 10.3 years, 124 of 65,589 participants of the HUNT II study, a Norwegian population, progressed to stage 5 chronic kidney disease. Former- and current-smokers less than 70 years of age at inclusion had significant multi-adjusted hazard ratios of 3.32 and 4.01 for kidney failure compared to those who never smoked. In men, the risk increased with a significantly higher trend for cumulative smoking (pack-years); however, the risk significantly decreased with increased elapsed years since smoking cessation. Although the prevalence of current smoking did not differ between genders, females had smoked less (10.2 compared to 15.8 pack-years) and the number of kidney failure cases was lower in females than in men (46 compared to 78). The effect of smoking on the risk of kidney failure was similar (hazard ratios of 2.94 and 4.30 in current-smoking women and men, respectively), but did not reach statistical significance in women. Thus, in this large population-based sample, we found that smoking is a significant risk factor for future kidney failure. Smoking cessation decreased this risk, at least in men.