Purpose To determine the incidence of deep vein thrombosis and pulmonary embolism in two cohorts representing regions of the United States. Methods The sample comprised 21,680 participants of the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study. Subjects were aged ≥45 years, resided in six communities, and were followed for 7.6 years. All hospitalizations were identified and thromboses were validated by chart review. Results The age-standardized incidence of first-time venous thromboembolism was 1.92 per 1000 person-years. Rates were higher in men than women, and increased with age in both sexes. There was no antecedent trauma, surgery, immobilization, or diagnosis of cancer for 48% (175/366) of events. The 28-day case-fatality rate was 11% (29/265) after a first venous thromboembolism and 25% (17/67) for cancer-associated thrombosis. The recurrence rate 2 years after a first venous thromboembolism was 7.7% per year (95% confidence interval [CI]: 4.5% to 10.9% per year). Cancer was the only factor independently associated with 28-day fatality (relative risk [RR] = 5.2; 95% CI: 1.4 to 19.9) or recurrent thrombosis (RR = 9.2; 95% CI: 2.0 to 41.7). Conclusion The incidence of venous thromboembolism in this cohort of middle- and older-aged subjects was similar to that observed in more geographically homogenous samples. Half of cases were idiopathic. Short-term mortality and 2-year recurrence rates were appreciable, especially among subjects with cancer. Based on this study we estimate that 187,000 cases of first-time venous thromboembolism are diagnosed yearly in the United States among those aged 45 years or older.