First-degree relatives of colorectal cancer patients are at increased risk for this malignancy which, in certain families, has right-sided predilection. For both these reasons, some clinicians recommend colonoscopy as the initial screening examination for these relatives. We used the results of a screening program of families of colon cancer patients to determine whether the tumor yield and costs justified this recommendation. Our study included 468 asymptomatic, first-degree relatives of large bowel neoplasia patients. Of these, 429 had only one relative with colorectal neoplasia and 39 had two or more such relatives. Persons with one affected relative were screened by fecal occult blood and flexible sigmoidoscopy, followed by colonoscopy if either test was positive, whereas colonoscopy was used as the primary screening test for those with two or more relatives with colorectal neoplasia. The comparison group included 452 persons without this family history of large bowel neoplasia. They were screened with fecal occult blood tests and flexible sigmoidoscopy. Based on a range of costs in the United States, and taking into account the hypothetical increased yield of screenees with neoplasia detected if colonoscopy was used as the primary screening examination, calculations of costs indicate that screening asymptomatic adults by colonoscopy is markedly (4-fold) more cost-effective if they have two or more first-degree colon cancer relatives. Otherwise, screening families with only 1 affected relative by flexible sigmoidoscopy, together with fecal occult blood, would seem the most economic method.