There is currently no standard therapeutic regimen available for patients with advanced colorectal cancer in whom the disease continues to progress after 2 or more lines of chemotherapy. The purpose of this study is to investigate the efficacy and safety of apatinib in patients with advanced colorectal cancer for whom at least two lines of prior chemotherapy had failed.Twenty seven patients with advanced colorectal cancer who had failed at least 2 lines chemotherapy were treated with apatinib (500 mg/day). As a comparison control, 26 advanced colorectal cancer patients with comparable clinical baseline characteristics including age, sex, Eastern Cooperative Oncology Group (ECOG) score, pathological type, carcinoembryonic antigen (CEA) level, tumor location, number and location(s) of metastasis, and previous chemotherapies were subject to observation. Survival analyses were performed via the Kaplan-Meier method. The toxicity were evaluated in all patients this study according to the National Cancer Institute Common Toxicity Criteria 4 (NCI CTC version 4.0).A total of 53 well-matched patients with advanced colorectal cancer were retrospectively analyzed. The median follow-up time was 6.0 months (2.0-16.0 months). The median PFS was significantly longer for apatinib group than for observation group (2.0 vs. 1.1 months; HR = 3.88; 95% confidence interval [CI], 1.91-7.88; P < .001). However, there was no significant difference between the 2 groups for median OS (5.0 vs. 4.0 months; HR = 1.03; 95% CI, 0.56-1.90; P = .914). The disease control rate of the apatinib group was significantly better than that of the observation group (70.4% vs 26.9%, P = .002). There was no significant difference in the overall remission rate between the 2 groups (3.7% vs 0%, P = .322). Advanced colorectal cancer patients with 2 or fewer metastatic sites experienced longer PFS than those with more than 2 sites. High ECOG scores, cancer localization to the right side of colon and lymph node metastasis were associated with increased risk of death and all remained independent factors affecting OS. The most common grade 3/4 treatment-related adverse events were hypertension and hand-foot skin syndrome.Apatinib treatment for patients with advanced colorectal cancer who had failed chemotherapy achieved better disease control and prolonged PFS relative to untreated controls. The toxicity was manageable.