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Supplemental Digital Content is available in the text BACKGROUND The role of the positive end-expiratory pressure (PEEP) and lung recruitment manoeuvre (LRM) combination (termed open-lung strategy, OLS) during intra-operative mechanical ventilation is not clear. OBJECTIVE To determine whether an open-lung strategy constituting medium PEEP (6–8 cmH2O) and repeated LRMs protects against postoperative complications in at-risk patients undergoing laparoscopic colorectal cancer resection under low-tidal-volume ventilation. DESIGN A prospective, assessor-blinded, randomised controlled trial. SETTING Single university-affiliated hospital, conducted from January 2017 to October 2018. PATIENTS A total of 280 patients at risk of pulmonary complications, scheduled for laparoscopic colorectal cancer resection under general anaesthesia and low-tidal-volume (6–8 ml kg−1 predicted body weight) ventilation. INTERVENTION The patients were randomly assigned (1 : 1) to a PEEP of 6–8 cmH2O with LRMs repeated every 30 min (OLS group) or a zero PEEP without LRMs (non-OLS group). MAIN OUTCOME MEASURES The primary outcome was a composite of major pulmonary and extrapulmonary complications occurring within 7 days after surgery. The secondary outcomes included intra-operative potentially harmful hypotension and the need for vasopressors. RESULTS A total of 130 patients from each group were included in the primary outcome analysis. Primary outcome events occurred in 24 patients (18.5%) in the OLS group and 43 patients (33.1%) in the non-OLS group [relative risk, 0.46; 95% confidence interval (CI), 0.26 to 0.82; P = 0.009). More patients in the OLS group developed potentially harmful hypotension (OLS vs. non-OLS, 15% vs. 4.3%; P = 0.004) and needed vasopressors (25% vs. 8.6%; P < 0.001). CONCLUSION Among at-risk patients undergoing laparoscopic colorectal cancer resection under low-tidal-volume ventilation, an open-lung strategy with a PEEP of 6–8 cmH2O and repeated LRMs reduced postoperative complications compared with a strategy using zero PEEP without LRMs. Of note, LRMs should be used with caution in patients with haemodynamic instability. TRIAL REGISTRATION Clinicaltrials.gov identifier: NCT03160144.