Alcohol interferes with folate metabolism and has opposing effects on the risks of cardiovascular disease and cancer. The authors examined the joint association of alcohol and folate intake with risk of major chronic disease, defined as fatal or nonfatal cardiovascular disease or cancer, or other nontraumatic death. This study included 83,929 women aged 34-59 years with no previous history of cardiovascular disease or cancer who provided dietary data in 1980. During 16 years of follow-up, the authors documented 10,666 new cases of major chronic disease. Overall, heavy drinkers (>30 g/day) with a lower total folate intake (<180 micro g/day) had the highest risk; in comparison with abstainers with a folate intake of 400-599 micro g/day, the multivariate relative risk was 1.36 (95% confidence interval: 1.10, 1.70). However, the increased risk of major chronic disease associated with heavy drinking was largely diminished among women with a higher folate intake (p for interaction = 0.02). The positive association between heavy alcohol/low folate intake and risk of major chronic disease was most apparent among women younger than age 60 years. Adequate folate intake may be important in the primary prevention of overall major chronic disease in women, especially among younger women consuming more than two alcoholic drinks per day.