Abstract: To evaluate the efficacy and safety of the combination of the XELOX regimen (oxaliplatin plus capecitabine) and thalidomide as the first-line treatment for metastatic colorectal cancer ( MCRC ). Methods: A total of 89 patients with MCRC who fulfilled all predetermined criteria were randomly assigned to the treatment and control group. The 44 patients in the treatment group received a combination of the XELOX regimen and thalidomide. The 45 patients in the control group received only the XELOX regimen. Each patient received at least two cycles ( 1 cycle = 21 d ) of treatment. The primary endpoint  was progression-free survival ( PFS ), and the second endpoints were objective response rate ( ORR ) as well as disease control rate ( DCR ). Drug safety and quality of life were also assessed. Results: The median PFS of the treatment and control groups were 5.6 and 5.2 months, respectively. The difference did not have statistical significance ( P = 0.307 ). The ORR of the 2 groups also had no statistical difference ( 34.1% vs. 26.7%, P = 0.446 ). The addition of thalidomide to XELOX significantly improved the DCR ( 63.6% vs. 42.2%, P = 0.043 ). Among the 24 patients with hepatic metastasis in the treatment group, 2 patients reached the surgical criteria after treatment. None of the patients in the control group did. Grades 3-4 constipation in patients treated with thalidomide was significantly elevated ( 20.5% vs. 4.4%, P = 0.022 ), but did not warrant drug discontinuation. The incidence rate of lethargy was elevated, but the difference was not statistically significant ( 13.6% vs. 4.4%, P = 0.130 ). The quality of life between the 2 groups had no statistical difference. Conclusion: A combination of XELOX and thalidomide as the first-line treatment in MCRC patients was well-tolerated. Statistically significant improvements were achieved for the DCR, but not for PFS.