Summary Background The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than sequential administration of the same drugs in patients with advanced colorectal cancer. Methods We randomly assigned 820 patients with advanced colorectal cancer to receive either first-line treatment with capecitabine, second-line irinotecan, and third-line capecitabine plus oxaliplatin (sequential treatment; n=410) or first-line treatment capecitabine plus irinotecan and second-line capecitabine plus oxaliplatin (combination treatment; n=410). The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov with the number NCT00312000. Findings 17 patients (nine in the sequential treatment group, eight in the combination group) were found to be ineligible and were excluded from the analysis. 675 (84%) patients died during the study: 336 in the sequential group and 339 in the combination group. Median overall survival was 16·3 (95% CI 14·3–18·1) months for sequential treatment and 17·4 (15·2–19·2) months for combination treatment (p=0·3281). The hazard ratio for combination versus sequential treatment was 0·92 (95% CI 0·79–1·08; p=0·3281). The frequency of grade 3–4 toxicity over all lines of treatment did not differ significantly between the two groups, except for grade 3 hand-foot syndrome, which occurred more often with sequential treatment than with combination treatment (13% vs 7%; p=0·004). Interpretation Combination treatment does not significantly improve overall survival compared with the sequential use of cytotoxic drugs in advanced colorectal cancer. Thus sequential treatment remains a valid option for patients with advanced colorectal cancer.