OBJECTIVES: To describe the demographic and clinical characteristics and comorbidities of colorectal cancer (CRC) patients and to evaluate the disease-specific expenditures (i.e., insurer-paid costs and patient-incurred out-of-pocket [OOP] expenses) incurred by CRC patients with one, two, and three or more lines of therapy. METHODS: Data were from the Thomson Reuters MarketScan® Research Databases. The analysis population included patients ≥18 years with incident CRC during 2005-2009 who utilized one or more lines of CRC therapy (defined by a 90-day gap in treatment or initiation of a new regimen).  Demographic characteristics, health status indices, and comorbidities were measured at baseline and/or during follow-up.  Expenditure data (i.e., paid amounts of adjudicated claims) were collected for patients while on therapy. OOP expenses were coinsurance and copayments.  Average per-patient monthly expenditures (2009 US dollars) were calculated in composite for all patients from initiation of first-line therapy through follow-up, and also disaggregated by each line of therapy. RESULTS: Among 13,670 CRC patients, 9,224 (67.5%) had exactly one line of therapy, 2,836 (20.7%) had exactly two lines, and 1,610 (11.8%) had three or more lines of therapy.  Total per-patient expenditures for first-line therapy averaged $12,067 per month, but increased to $13,312 for patients transitioning to second-line therapy, and to $14,651 for patients transitioning to third-line therapy. Monthly OOP expenses were a small (about 2%) contributor to total costs, ranging from $241, $246, and $238 by respective lines of therapy. Total monthly expenditures for patients covered by commercial insurance were substantially (>50%) higher than for patients covered by Medicare supplemental insurance. CONCLUSIONS: Ranging from about $12,000 to $15,000 per month by increasing lines of therapy, direct costs of CRC present a significant economic burden to health plans and self-insured employers.  Patient-borne OOP expenses are relatively small but meaningful contributors to the overall financial burden imposed by CRC.