Brain metastases (BM) occur in approximately 20-40% of cancer patients. The present study investigated the clinical outcomes of patients with BM from colorectal cancer (CRC) to assess the benefit of systemic chemotherapy (CT) administered after surgical or radiotherapeutic control of BM and to identify independent prognostic factors associated with survival after BM. Between August 2001 and July 2009, 118 patients with symptomatic BM from CRC received either cranial irradiation or craniotomy at two large cancer centers in South Korea. Retrospective review and statistical analysis of clinical characteristics and outcomes were performed for all patients. Median time from diagnosis of metastatic CRC to detection of BM was 12.2 months (range 0-76.2 months). Thirteen patients (11%) exhibited brain involvement at initial presentation. Median survival after BM development was 4.1 months [95% confidence interval (CI) 3.3-4.9 months]. Forty-six patients (40%) had been treated previously with the chemotherapeutic agents fluoropyrimidine, oxaliplatin, and irinotecan. Patients who received CT after BM exhibited significantly improved survival compared with those who did not (12.4 versus 3.1 months, respectively; P < 0.001). Multivariate analysis revealed that CT intervention after presentation with BM was significantly associated with survival after BM, and the adjusted hazard ratio was 0.30 (95% CI 0.17-0.51, P < 0.001). Although BM is a late-stage phenomenon in CRC, approximately two-thirds of patients were still unexposed to irinotecan or oxaliplatin at the development of BM in our study. Thus, additional chemotherapeutic intervention after BM associated with CRC may be beneficial for selected patients.