Objective: We evaluated the bladder cancer risk associated with coffee consumption in a case–control study in Spain and examined the gene–environment interactions for genetic variants of caffeine-metabolizing enzymes. Methods: The analyses included 1,136 incident cases with urothelial carcinoma of the urinary bladder and 1,138 controls. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for area, age, gender, amount of cigarette smoking, and years since quitting among former smokers. Results: The OR (95% CI) for ever consumed coffee was 1.25 (0.95–1.64). For consumers of 1, 2, 3, and 4 or more cups/day relative to never drinkers, OR were, respectively, 1.24 (0.92–1.66), 1.11 (95% CI 0.82–1.51), 1.57 (1.13–2.19), and 1.27 (0.88–1.81). Coffee consumption was higher in smokers compared to never smokers. The OR for drinking at least 4 cups/day was 1.13 (0.61–2.09) in current smokers, 1.57 (0.86–2.90) in former smokers, and 1.23 (0.55–2.76) in never smokers. Gene–coffee interactions evaluated in NAT2, CYP1A2, and CYP2E1-02 and CYP1A1 were not identified after adjusting for multiple testing. Conclusion: We observed a modest increased bladder cancer risk among coffee drinkers that may, in part, be explained by residual confounding by smoking. The findings from the gene–coffee interactions need replication in further studies.