Objective This systematic review was conducted to investigate the efficacy and safety of thalidomide in metastatic breast cancer (MBC).Methods Based on pre-defined inclusion and exclusion criteria, data were independently collected from different databases by three investigators. Overall, three studies were included. Results The included studies indicated that no patient achieved a partial or complete response from different thalidomide dose levels. Thalidomide was well-tolerated at doses of 100 mg, 200 mg, and 400 mg. In all three studies, common side effects included constipation, somnolence, fatigue, peripheral neuropathy, and dry mouth. Circulating angiogenic factors were not significantly correlated with disease progression. Conclusion The available evidence indicates that single-agent thalidomide has little or no activity in patients with MBC.