Objective To evaluate the safety and efficacy of CapeOx(XELOX) chemotherapy combined with hyperthermia in treating patients with advanced colorectal cancer. Methods A total of 80 patients with advanced colorectal cancer were evenly randomized into two groups: the combined group underwent CapeOx (XELOX) chemotherapy and hyperthermia(on the 1^st, 5^th, and 10^th days of chemotherapy), while the control group only received chemotherapy. The treatment efficacies (evaluated by Response Evaluation Criteria in Solid Tumors[RECIST]), serum levels of carcinoembryonic antigen (CEA) and adverse reactions were compared between the two groups. The survival rates of two groups were recorded and analyzed. Results RECIST results showed that the rate of complete remission plus partial remission in combined group was 67.5%(27/40), which was significantly higher than that in the control group (35.0%[14/40], P<0.05). The serum levels of CEA were decreased in both group after treatment, with that in the combined group being significantly lower than that in the control group( [101.3±58.1] vs [213.6±100.3] ng/mL, P<0.05). The adverse reaction(leukocyte decrease, gastrointestinal reaction, and peripheral nerve reaction) rate of the combined group was significantly lower than that in the control group(P<0.05). The 2-month survival rates were 100.0% in both groups (P>0.05); while the 2-year survival rate of the combined group was significantly higher than that in the control group (37.5%[15/40] vs 12.5%[5/40], P<0.05). Conclusion CapeOx (XELOX) chemotherapy combined with hyperthermia is safe and effective to control the growth of advanced colorectal cancer, benefiting the survival and decreasing the adverse reaction.