Aim: To evaluate the association of alcohol and smoking combined with cardiovascular and renal events and investigate whether moderate and heavy alcohol consumption have a different impact on this association. Methods: The study was conducted in 1208 young-to-middle-age stage 1 hypertensive patients. Subjects were classified into three categories of cigarette smoking and alcohol use, and the risk of adverse outcomes was assessed over a 17.4-year follow-up. Results: In multivariable Cox models, smoking showed a different prognostic impact on alcohol drinkers and abstainers. In the former, an increase in the risk of cardiovascular and renal events was observed compared to nonsmokers (hazard ratio, 2.6, 95% CI, 1.5–4.3, p < 0.001), whereas in the latter, the risk did not achieve the level of statistical significance (p = 0.27) with a significant interaction between smoking and alcohol use (p < 0.001). Among the heavy smokers who also drank alcoholic beverages, the hazard ratio from the fully adjusted model was 4.3 (95% CI, 2.3–8.0, p < 0.0001). In the subjects with moderate alcohol consumption, the risk of smoking and alcohol combined was similar to that found in the whole population (hazard ratio, 2.7; 95% CI, 1.5–3.9, p < 0.001). Among the subjects with heavy alcohol consumption, the hazard ratio was 3.4 (95% CI, 1.3–8.6, p = 0.011). Conclusion: These findings indicate that the detrimental cardiovascular effects of smoking can be worsened by concomitant alcohol use. This synergistic effect occurs not only for heavy alcohol consumption but also for moderate use. Smokers should be aware of the increased risk associated with concomitant alcohol consumption.