Background: Psychological distress occurs frequently in patients with cancer. Effective management requires targeted selection of patients (T), followed by enhanced care (E), and the application of stepped care for psychological distress (S). This study aimed to evaluate the effectiveness of a screening and stepped care program (the TES program) compared to usual care in reducing psychological distress in patients with metastatic colorectal cancer (mCRC) starting with first line systemic treatment. Methods: In this cluster randomized trial, 16 hospitals were assigned to either the TES program or care as usual (CAU). Patients in the TES arm were screened for psychological distress with the Hospital Anxiety and Depression Scale (HADS) and Distress Thermometer/Problem List (at baseline, 10 and 18 weeks). Stepped care was offered to those with distress, as well as to patients expressing the need for psychosocial care. Stepped care consisted of watchful waiting, guided self-help, face-to-face problem-solving therapy, or referral to specialized mental health care. The primary outcome was change in psychological distress over time (HADS); secondary outcomes were quality of life (QOL), satisfaction with care and recognition and referral of distressed patients by clinicians. Measures were assessed at baseline, after 3, 10, 24 and 48 weeks of follow-up. Linear mixed models were used to evaluate the outcome. Results: A total of 349 patients were included; 184 to the TES program and 165 to CAU. In the TES arm, 60.3% of the patients screened positive for psychological distress; 26.1% of patients entered the stepped care program (14.7% only used watchful waiting, and 11.4% used at least one of the following steps).There was no difference in the course of psychological distress over time between treatment groups (p > 0.05). The TES group reported higher satisfaction with the received treatment over time and better cognitive QOL (all p-values < 0.05). Conclusions: Screening and subsequent treatment for psychological distress does not improve psychological distress. Our results suggest that enhanced discussion of psychosocial concerns may improve aspects of patient’s well-being. Clinical trial information: NTR4034.