No previous prospective US study has examined whether the incidence of colorectal cancer (CRC) is disproportionately high in low socioeconomic status (SES) populations of both men and women. This study examined the relationship between both individual and area-level SES and CRC incidence, overall and by tumor location. Data were obtained from the ongoing prospective National Institutes of Health-AARP Diet and Health Study of persons (50-71 years old) who resided in 6 US states and 2 metropolitan areas at baseline in 1995-1996. Incident CRCs were ascertained from tumor registries through December 2006. SES was measured by self-reported education and census-tract socioeconomic deprivation. Baseline and follow-up questionnaires collected detailed information on individual-level CRC risk factors including family history and health behaviors. Among 506,488 participants analyzed, 7676 were diagnosed with primary invasive colorectal adenocarcinomas: 44.6% corrected in the right colon, 26.7% in the left colon, and 25.9% in the rectum. The overall incidence of CRC was significantly higher among people who had low educational level or lived in low-SES neighborhoods, relative to respective highest-SES groups, even after accounting for other risk factors. These associations were stronger in the rectum than in left or right colon. In the right colon, there were no significant SES differences by either SES measure after accounting for covariates. SES, assessed by either individual-level education or neighborhood measures, was associated with risk of CRC even after accounting for other risk factors. The relationship between SES and CRC was strongest in the rectum and weakest in the right colon.