OBJECTIVES: To examine the factors associated with total health care expenditures in newly diagnosed subjects with colorectal cancer (CRC) receiving systemic therapy. METHODS: Patients ages 18-63 years when newly diagnosed with CRC between January 1, 2005 and June 31, 2009 receiving systemic therapy were identified using a large, US-based administrative medical claims (MarketScan) database. 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. Generalized linear regression models were used to estimate total medical expenditures (outcome variable) as a function of number of lines of therapy (key independent variable) and demographic/clinical covariates. The excess expenditures associated with additional lines of therapy were estimated as the difference between predicted medical expenditures for those with 1st line of therapy versus 2nd and 3rd + lines of therapy. RESULTS: A total of 5160 subjects were included with the majority being male (55%) and between ages 51-60 years (52%). After adjusting for demographic, and clinical covariates (comorbidities, metastasis development, and post-index CRC surgery and radiation) and follow-up days, the mean annualized total health care costs (N=5,160) were predicted to be $67,902. Use of 2nd line and 3rd line + therapies was associated with an annualized incremental costs of $11,662 [95% confidence interval (CI): $8,581-$14,876] and $43,313 (95% CI: $43,313-$49,401), respectively. Age, gender, region, index year of diagnosis, post-index CRC surgery and/or radiation, development of metastasis (p-value <0.0001), presence of vascular comorbidities (p-value=0.02), plan type (p-value=0.04) and use of first line bevacizumab (p-value=0.0002) were all associated with statistically significant increased likelihood of costs. CONCLUSIONS: Additional lines of therapy and use of first line biologics increased the cost of treatment substantially in CRC patients.