OBJECTIVES: Clinical data supports the use of molecular profiling (MP) to inform therapeutic decisions. In particular, evidence suggests the selection of pharmacotherapy for metastatic colon cancer (mCRC) patients could be further improved by enhancing biomarker informed decision-making.  While the clinical data is compelling, our objective was to explore the economic consequences of adopting a commercial MP approach with accompanying therapeutic recommendations (Caris Target Now™) from a payer perspective via a detailed cost-offset model. METHODS:  Therapeutic recommendations based on a MP approach were compared to current treatment patterns to determine the change in treatment mix and associated treatment costs.  Biomarker selection was based on a systematic review of the literature and grading the evidence to support clinical benefit for a specific treatment choice.  Oncologists were interviewed to inform and validate modeled treatment pathways based on patterns of biomarker expression in the patient's tumor. Biomarkers evaluated include: BRAF, KRAS, NRAS, PI3KCA, PTEN, EGFR, TOP1, ERRC1, TS, and EML4-ALK. RESULTS: In our model, approximately 29% of patients who test positive for response to EGFR inhibitor therapies, under current clinical treatment protocol, have additional biomarkers with compelling data to suggest non-responsiveness.  These same patients display biomarkers indicating potential benefit of other drugs.  Biomarker-associated change in therapy as suggested by MP, yielded an annual savings of $7.3k per mCRC patient.  The adoption of this MP service provided net cost-benefit; treatment costs avoided were substantially higher (232%) than the testing cost. CONCLUSIONS: Molecular profiling, including analysis of oncoproteins, gene expression and specific gene mutations, may add significant economic value to the treatment of cancer patients by directing treatments to those most likely to respond.  The cost-offsets associated with biomarker-based therapy choice lead to more rational use of high-cost drugs.  Implementing therapy for mCRC based on a multi-biomarker, decision-support approach may have potential to improve patient care and decrease costs.