OBJECTIVES: Treatment patterns and cost of care are believed to vary substantially as patients with colorectal cancer (CRC) progress from first line through third line therapy.  The aim of this study was to examine patterns and cost of care in these patients. METHODS: A retrospective analysis was performed using claims from the Optum Oncology Research Database. Patients aged 18 years and older, diagnosed with CRC between July 1, 2004 and December 31, 2010, who were insured by a commercial health plan were included in the study.  Chemotherapy combinations were assessed for patients receiving first, second and third line of therapy for CRC; and for patients with and without metastatic disease.  Inpatient, outpatient, chemotherapy, biologic-related, and total costs were compared by the Kruskal-Wallis test. RESULTS: A total of 1039 patients who received chemotherapy or biologic therapy for CRC were included. FOLFOX and fluorouracil monotherapy were the most common first-line therapies, each accounting for approximately 27% of patients who received any chemotherapy.  Oxaliplatin-based regimens were most common for patients receiving second-line therapy (45% of patients).   Irinotecan-based regimens were most common among patients receiving third line therapy (35% of patients).  The median total cost of care increased significantly for patients receiving first ($25,782), second ($36,951), and third ($86,944) line therapy (p<0.0001 by Kruskal-Wallis test). Median costs were significantly greater for patients receiving third versus first line therapy for outpatient care ($39,952 vs. $15,521), inpatient care ($3,668 vs. $1,721 vs.), chemotherapy ($14,059 vs. $3,662) and biologic therapy ($28,824 vs. $4,899).  Median total were significantly greater for patients with metastases ($39,001) compared with those without ($8,989; p<0.0001). CONCLUSIONS: Treatment patterns vary significantly by line of therapy in patients with CRC.  The total cost of care increased significantly as patients received additional lines of therapy and is significantly greater for patients with metastases compared to those without.