Background & Aims: Although a number of epidemiologic studies have found dietary fiber and whole grains to be inversely associated with colorectal cancer incidence, studies of dietary and other risk factors for small intestinal cancer have been sparse and all of a case-control design. We conducted a prospective cohort study to determine the relationship between intake of dietary fiber/whole grains and the incidence of small intestinal cancer. Methods: We analyzed dietary data collected in 1995 and 1996 from 293,703 men and 198,618 women in the National Institutes of Health-AARP Diet and Health Study. We used multivariate Cox proportional hazards models to estimate relative risk (RR) and 2-sided 95% confidence intervals (CIs) for quintiles of dietary fiber and whole grain intake. Results: Through 2003, 165 individuals developed small intestinal cancers. Dietary fiber/whole grain intake was generally associated with a lower risk of small intestinal cancer. The multivariate RRs (95% CIs; 5th vs 1st intake quintile) were 0.79 (0.43-1.44; P trend, .41) for total dietary fiber, 0.51 (0.29-0.89; P trend, .01) for fiber from grains, and 0.59 (0.33-1.05; P trend, .06) for whole grain foods. Conclusions: Intake of fiber from grains and whole-grain foods was inversely associated with small intestinal cancer incidence; the RR values were consistent with those from the same dietary factors for large bowel cancer in this cohort. In conjunction with the anatomic and physiologic commonalities of the large and small bowel, as well as the mutually increased risks for second cancer for both organs, grain fiber and whole grain foods seem to protect against lower gastrointestinal cancers.