OBJECTIVES: This study examined total health care expenditures in newly diagnosed subjects with colorectal cancer (CRC) over time and by lines of therapy received. METHODS: Patients aged 18-years and older when newly diagnosed with CRC between January 1, 2005 and June 31, 2009 were identified using a large, US-based administrative medical claims (MarketScan) database. Patients were identified with CRC if they had an ICD-9-CM claim for a primary diagnosis of colon or rectal cancer on 2 different days but within 180 days of each other. At least 6 months of patient history prior to CRC diagnosis and at least 1-year post-index continuous enrollment was required. Patients were followed from initial CRC diagnosis (index date) to disenrollment or June 31, 2010. Chemotherapy and biologic treatments over time were analyzed to identify lines of therapy. Total health care costs included costs associated with CRC and other comorbidities. Univariate analyses were performed to examine changes in costs over time and with increasing lines of therapy. RESULTS:  A total of 23,547 subjects were included with a mean age of 65.3 years, 49% were over 65 years, and 52% were males. They were predominately from the South (40%) and the Midwest region (36%) and majority (54%) were enrolled in a preferred provider organization plan. 63% of the subjects received no systemic treatment for CRC and 17%, 13%, and 7% received 1st line only, 2nd line only and 3rd + lines of treatment for CRC, respectively. The mean annualized costs increased from $20,785 to $50,255 for those diagnosed in 2005 to 2009 (p-value <0.001). The mean annualized costs for those receiving 1st line only, 2nd line only and 3rd + lines of treatment were $46,277, $69,244, and $108,819, respectively. CONCLUSIONS: Annualized total health care costs in newly diagnosed CRC subjects more than doubled from 2005 to 2009 growing faster than medical inflation.