AIM Chronomodulated chemotherapy has been reported to be superior to conventional chemotherapy, but the results from randomized controlled trials (RCTs) are inconsistent. We performed a meta-analysis to summarize the efficacy and safety of chronomodulated chemotherapy for patients with metastatic colorectal cancer. METHODS A literature search for relevant RCTs comparing the efficacy and safety of chronomodulated chemotherapy and conventional chemotherapy was performed. The main outcomes were overall survival (OS), objective response rate (ORR) and toxicity (grade 3/4), which included vomiting and nausea, diarrhea, mucositis, neutropenia and peripheral sensory neuropathy. Pooled relative risks (RRs) and hazard ratios (HRs) with their 95% confidence intervals (95% CIs) were estimated. RESULTS Six RCTs involving 1347 patients were included. Chronomodulated chemotherapy showed no advantages for OS (HR = 0.95; 95% CI, 0.84-1.08; P = 0.463) or ORR (RR = 1.06; 95% CI, 0.81-1.39; P = 0.499). The two groups were similar in terms of grade 3/4 vomiting and nausea (RR = 1.02; 95% CI, 0.78-1.35; P = 0.872), diarrhea (RR = 1.44; 95% CI, 0.87-2.36; P = 0.149) or peripheral sensory neuropathy (RR = 0.86; 95% CI, 0.56-1.34; P = 0.512), whereas decreased risks of mucositis (RR = 0.31; 95% CI, 0.14-0.66; P = 0.000) and neutropenia (RR = 0.40; 95% CI, 0.27-0.57; P = 0.000) were observed in chronomodulated chemotherapy. CONCLUSION Chronomodulated chemotherapy may be favorable to reduce the risks of certain side effects, but there is no current evidence for improvement in OS or ORR. Our analysis suggests that the available data does not support the use of chronomodulated chemotherapy.