Background: Few studies have investigated psychosocial characteristics and lifestyle behaviors of participants at programs for secondary prevention of colorectal cancer (CRC). This study aimed, through a comprehensive psychosomatic assessment based on clinimetric principles, to evaluate psychosocial characteristics and lifestyle behaviors in participants at CRC secondary prevention program, and to investigate the associations between these variables and endoscopic outcomes. Methods: In this cross-sectional study, the first 150 consecutive asymptomatic participants at the CRC prevention program who resulted positive to fecal occult blood test (FOBT) and were thus referred to colonoscopy, underwent a psychosomatic assessment including psychiatric diagnoses (DSM-5), psychosomatic syndromes (DCPR-R), psychological distress (SQ), psychological well-being (PWB-I) and lifestyle behaviors. Results: Whereas only 5.3% of the sample showed at least one DSM-5 diagnosis, 51.3% showed at least one DCPR syndrome, such as allostatic overload, alexithymia, Type A behavior, and demoralization. Patients affected by psychosomatic syndromes presented with significantly higher psychological distress, lower psychological well-being and unhealthy lifestyle behaviors, such as tobacco smoking and unhealthy diet, in comparison with patients without DCPR syndromes. Among endoscopic outcomes, the presence of adenomas was significantly associated with DCPR irritable mood. Conclusions: In a clinical context of secondary prevention addressing asymptomatic patients with a positive FOBT, a comprehensive psychosomatic assessment may provide relevant clinical information for those patients who present certain psychosomatic syndromes associated with high psychological distress, impaired psychological well-being, unhealthy lifestyle behaviors and colorectal precancerous lesions. The results of the present study indicate a road to the practice of “preventive” medicine at CRC screening program.