||PURPOSE: Small intestinal cancer is increasing in the U.S.A, yet little is known about its etiology. Our aim was to prospectively evaluate risk factors for this malignancy by the two main histologic subtypes (adenocarcinomas and carcinoids). METHODS: Hazard ratios and 95% confidence intervals (CI) were estimated for all incident small intestinal cancers (n = 237), adenocarcinomas (n = 84), and malignant carcinoids (n = 124), by demographic and lifestyle factors among 498,376 men and women. RESULTS: Age was the only risk factor for adenocarcinomas (HR for ≥ 65 vs. 50-55 years = 3.12, 95% CI 1.33, 7.31). Age (HR for ≥ 65 vs. 50-55 years = 3.31, 95% CI 1.51, 7.28), male sex (HR = 1.44, 95% CI 1.01, 2.05), body mass index (BMI, HR for ≥ 35 vs. 18.5-< 25 kg/m2 = 1.95, 95% CI 1.06, 3.58), and current menopausal hormone therapy use (HR = 1.94, 95% CI 1.07, 3.50) were positively associated with malignant carcinoids. A family history of any cancer or colorectal cancer (HR = 1.42, 95% CI 0.99, 2.03; 1.61, 0.97, 2.65, respectively), or a personal history of colorectal polyps (HR = 1.51, 95% CI 0.92, 2.46) produced elevated, but not statistically significant, risks for malignant carcinoids. Race, education, diabetes, smoking, physical activity, and alcohol intake were not associated with either histologic subtype. CONCLUSIONS: Risk factors differed according to cancer subtype; only age was associated with adenocarcinomas, whereas age, male sex, BMI, and menopausal hormone therapy use were positively associated with malignant carcinoids.