Abstract Background Infectious complications and anastomotic leakage affect approximately 30 per cent of patients after colorectal cancer surgery. The aim of this multicentre randomized trial was to investigate whether selective decontamination of the digestive tract (SDD) reduces these complications of elective colorectal cancer surgery. Methods The effectiveness of SDD was evaluated in a multicentre, open-label RCT in six centres in the Netherlands. Patients with colorectal cancer scheduled for elective curative surgery with a primary anastomosis were eligible. Oral colistin, tobramycin and amphotericin B were administered to patients in the SDD group to decontaminate the digestive tract. Both treatment and control group received intravenous cefazolin and metronidazole for perioperative prophylaxis. Mechanical bowel preparation was given for left-sided colectomies, sigmoid and anterior resections. Anastomotic leakage was the primary outcome; infectious complications and mortality were secondary outcomes. Results The outcomes for 228 patients randomized to the SDD group and 227 randomized to the control group were analysed. The trial was stopped after interim analysis demonstrated that superiority was no longer attainable. Effective SDD was confirmed by interspace DNA profiling analysis of rectal swabs. Anastomotic leakage was observed in 14 patients (6·1 per cent) in the SDD group and in 22 patients (9·7 per cent) in the control group (odds ratio (OR) 0·61, 95 per cent c.i. 0·30 to 1·22). Fewer patients in the SDD group had one or more infectious complications than patients in the control group (14·9 versus 26·9 per cent respectively; OR 0·48, 0·30 to 0·76). Multivariable analysis indicated that SDD reduced the rate of infectious complications (OR 0·47, 0·29 to 0·76). Conclusion SDD reduces infectious complications after colorectal cancer resection but did not significantly reduce anastomotic leakage in this trial. Registration number: NCT01740947 (https://www.clinicaltrials.gov).