Tooth loss has been suggested as a potential risk factor for stroke. We conducted a prospective cohort study of stroke in Korea on hypertension, diabetes, smoking, and tooth loss to characterize their independent effects and interactions. The overall risk of stroke and the risk of different subtypes of stroke were evaluated in relation to tooth loss using Cox proportional hazards models among 867,256 Korean men and women, aged 30-95 years, who received health insurance from the National Health Insurance Corporation and were medically evaluated between 1992 and 1995, with tooth loss measured. The overall prevalence of having at least one tooth removed among the people in the study was 29.8% (31.9% for men and 22.3% for women). During a 14-year follow-up, 28,258 strokes with 5105 fatal strokes occurred. For men and women, tooth loss was associated with total stroke and stroke subtypes. In a multivariable model adjusting for selected covariates, a graded association between higher tooth loss and higher risk of total stroke was observed in men [> or =7 lost teeth versus 0 (hazard ratio (HR)=1.3; 95% confidence interval (CI), 1.2-1.4)] and in women (HR=1.2; 95% CI, 1.0-1.3). The HRs for ischemic and hemorrhagic stroke were also similar in men and women. There was evidence of interaction of hemorrhagic stroke risk with hypertension and tooth loss. Tooth loss is independently associated with increased risk of stroke and hypertension does interact antagonistically, particularly for hemorrhagic stroke.