The clinical significance of a distal colorectal polyp is uncertain. We determined the risk of advanced proximal neoplasia, defined as a polyp with villous features, a polyp with high-grade dysplasia, or cancer, among persons with distal hyperplastic or neoplastic polyps as compared with the risk among persons with no distal polyps. We analyzed data from 1994 consecutive asymptomatic adults (age, 50 years or older) who underwent colonoscopic screening for the first time between September 1995 and December 1998 as part of a program sponsored by an employer. The location and histologic features of all polyps were recorded. Colonoscopy to the level of the cecum was completed in 97.0 percent of the patients. Sixty-one patients (3.1 percent) had advanced lesions in the distal colon, including 5 with cancer, and 50 (2.5 percent) had advanced proximal lesions, including 7 with cancer. Twenty-three patients with advanced proximal neoplasms (46 percent) had no distal polyps. The prevalence of advanced proximal neoplasia among patients with no distal polyps was 1.5 percent (23 cases among 1564 persons; 95 percent confidence interval, 0.9 to 2.1 percent). Among patients with distal hyperplastic polyps, those with distal tubular adenomas, and those with advanced distal polyps, the prevalence of advanced proximal neoplasia was 4.0 percent (8 cases among 201 patients), 7.1 percent (12 cases among 168 patients), and 11.5 percent (7 cases among 61 patients), respectively. The relative risk of advanced proximal neoplasia, adjusted for age and sex, was 2.6 for patients with distal hyperplastic polyps, 4.0 for those with distal tubular adenomas, and 6.7 for those with advanced distal polyps, as compared with patients who had no distal polyps. Older age and male sex were associated with an increased risk of advanced proximal neoplasia (relative risk, 1.3 for every five years of age and 3.3 for male sex). Asymptomatic persons 50 years of age or older who have polyps in the distal colon are more likely to have advanced proximal neoplasia than are persons without distal polyps. However, if colonoscopic screening is performed only in persons with distal polyps, about half the cases of advanced proximal neoplasia will not be detected.