OBJECTIVES: To compare the clinical costs and complications of tissue-based biopsies to blood-based biopsies (GeneStrat^TM) for the purpose of biomarker testing in non-small cell lung cancer (NSCLC). METHODS: In this study, biomarker testing was compared using two tissue-based biopsy methods, CT-guided and navigational bronchoscopies versus blood draws used for the GeneStrat test. A Medicare reimbursement perspective was used in determining the costs of biopsies and blood draws, clinical complications, and pathology testing. Complication rates were obtained from publicly available clinical studies. RESULTS: In a hypothetical case where the biomarker results for EGFR, KRAS, ALK, and BRAF mutations were requested, blood-based test was the dominant procedure, costing the least ($836.45) and with no reported complications or hospitalizations associated with the blood draw. Biomarker testing via CT-guided biopsy was the second most expensive procedure costing on average $4,130.09 to perform but had the highest rate of complications with 15% of patients presenting some form of pneumothorax or lung collapse. Additionally, a small minority of patients suffer from hemorrhage (1%) and respiratory failure (0.68%) following the biopsy procedure. Complications resulted in hospitalization for 7.6% percent of patients. With complications, the cost of biopsy, treatment and testing can rise up to $18,567.23 per patient. Navigational bronchoscopies, although higher in price (mean cost of $8,283.62) resulted in fewer complications (1.6% pneumothorax, 0.1% respiratory failure leading to a 1% hospitalization rate). With complications, the cost of navigational bronchoscopy and testing can rise to $22,720.76. The dominance of blood testing was not sensitive to changes in price or complication rates. CONCLUSIONS: Biomarker testing via the blood-based GeneStrat test was both significantly cheaper and patients had fewer complications than both CT-guided biopsy and navigational bronchoscopy. Blood-based biopsies should be considered instead of tissue-based biopsies in all patients with a confirmed NSCLC diagnosis to establish tumor biomarker status.