Although several screening tests are now available, at present none of them has been proven the best one. Colonoscopy is usually used in high-risk subjects (family history of either colorectal cancer [CRC] or adenomas). In intermediate-risk subjects, fecal occult blood test (FOBT) is preferred, and colonoscopy is performed only when FOBT results positive. The aim of this study is to better define the role of colonoscopy in a screening program. Three groups of subjects were retrospectively reviewed. RSP (Regional Screening Program), FDR (First Degree Relatives), and Control-groups included 362, 581, and 300 subjects, respectively. Adenoma or carcinoma were more frequent in RSP-group than in FDR- and Control-group (53%, 23.7%, and 20%, respectively; p < 0.001). CRC rate was 11.6% in RSP-group, 2.2% in FDR-group (p < 0.001), 6% in Control-group (p < 0.05). Adenoma rate was 41.4% in RSP-group, 21.5% in FDR-group (p < 0.05), 14% in Control-group (p < 0.01). Our results showed that colonoscopy probably can not be regarded as a first-line tool for the screening of CRC in FDR of patients with CRC or adenoma. Some stratification or scoring system for the risk of CRC should be adopted. As an alternative, FOBT could be used also in these subjects.