Six hundred twenty-one asymptomatic persons with negative fecal occult blood tests (ages 50-75 yr), including 496 with no known risk factors for colorectal cancer and 125 with a single first-degree relative with a history of colonic neoplasia developed after age 40, underwent screening colonoscopy. Three Dukes A cancers were detected in average-risk persons. The overall prevalence of adenomatous polyps was 27%. Multiple logistic regression analysis revealed that increasing age and male gender were both strong predictors of colonic neoplasia (p < 0.001). A positive family history of a single first-degree relative with colorectal cancer was not associated with an increased prevalence of colonic neoplasia (p = 0.29), although an effect may be present if the relative was < 60 yr at diagnosis. Overall 16% of males and 7% of women > or = 60 yr had at least one adenoma that was large (> or = 1 cm in size), villous or tubulovillous, or had grade 3 dysplasia. We conclude that the prevalence of colonic neoplasia in asymptomatic persons with negative fecal occult blood tests is substantial, particularly in elderly males. A family history of a single first-degree relative diagnosed at age > or = 60 yr with colorectal cancer is not associated with an increased prevalence of colonic adenomas.