Background: Primary tumor resection (PTR) in patients with synchronous metastatic colorectal cancer (CRC) has been associated with a survival benefit in comparative cohort studies. In the CAIRO4 phase III randomized trial, the potential benefit of upfront PTR followed by systemic therapy versus systemic therapy alone was investigated. Methods: Main eligibility criteria included histologically confirmed CRC, unresectable metastases, resectable primary tumor in situ without related severe symptoms, and WHO performance status (PS) 0-2. Eligible patients were randomized to first-line fluoropyrimidine-based chemotherapy plus bevacizumab with or without upfront PTR strategy. Randomization was stratified for number of metastatic sites (1 versus more), institution, WHO PS (0-1 versus 2), serum LDH (normal versus > ULN), and location of the primary tumor (left versus right-sided). The primary endpoint was overall survival (OS), which was analyzed by intention-to-treat (ITT) using the MaxCombo test. The original sample size of 306 patients was amended to 206 participants due to slow accrual. With final primary analysis based on 181 events, the study had 71% power to detect the OS difference of 19 versus 13 months deemed clinically relevant in the original sample size calculation. The trial is registered as NCT01606098. Results: Between August 2012 and February 2021, 206 patients were randomized: 103 patients to each arm. Two patients in the upfront PTR arm were excluded due to ineligibility. A total of 204 patients (57% male, median age 65 [IQR 59 -71] years, 50% right-sided CRC and 98% WHO PS 0-1) were included with a median follow-up of 63.6 months. In the upfront PTR arm 5% of patients did not undergo PTR and 13% did not receive subsequent systemic therapy. In the arm without upfront PTR, 1% of patients did not receive systemic therapy. The median number of cycles was 9 [IQR 4-15] in the upfront PTR arm versus 11 [6-16] in the arm without upfront PTR. Median OS was 20.5 (95% CI 17.0 – 25.1) months in the upfront PTR arm and 18.3 (95% CI 16.0 – 22.2) months in the arm without upfront PTR (p = 0.345). Median PFS was 10.1 (95% CI 8.7-11.7) months in the upfront PTR arm and 10.1 (95% CI 8.6-11.8) months in the arm without upfront PTR (p = 0.805). At a later point in their disease course, 1.9% of patients in the arm without upfront PTR underwent a colostomy and 16.5% required PTR for symptom palliation. Conclusions: In patients with synchronous metastatic CRC amenable to palliative systemic therapy without severe symptoms related to the primary tumor, upfront PTR did not result in a significant median OS difference compared to immediate start with systemic treatment. Funding: This work was funded by the Dutch Cancer Society (grant KUN 2012-5697) and Hoffmann-La Roche Ltd. Clinical trial information: NCT01606098.