Objective: To evaluate the clinical, cost, and value implications of using epidermal growth factor receptor (EGFR) testing to guide treatment of refractory non-small cell lung cancer (NSCLC) patients compared to standard empirical treatments. Methods: We developed a decision analytic model to evaluate the cost-utility of using EGFR protein expression or EGFR gene copy number testing compared to standard treatments (erlotinib, docetaxel, or pemetrexed) in refractory advanced NSCLC patients using the societal perspective and a two-year time frame. Survival, cost, and utility inputs were obtained from publicly available sources. We evaluated the uncertainty in the model using one-way and probabilistic sensitivity analyses as well as an expected value of perfect information (EVPI) analysis. Results: In the base case, the lifetime QALY estimates ranged from 0.431 for docetaxel to 0.502 for gene copy number testing with pemetrexed for those testing negative (GC/PEM). Lifetime cost estimates ranged from $57,200 for erlotinib to $71,800 for pemetrexed. After removing dominated interventions, erlotinib dominated docetaxel, gene copy number testing with docetaxel for those testing negative (GC/DOC) had an ICER of $162,018/QALY versus erlotinib, and GC/PEM had an ICER of $2,487,867/QALY versus GC/DOC. The model results were most sensitive to overall survival, progression-free survival, health state utilities, and drug acquisition cost inputs. In the probabilistic sensitivity analyses, GC/DOC had a 14% probability of decreasing costs and an 83% probability of increasing QALYs versus Erlotinib. The discounted EVPI at a $100,000/QALY threshold in the US population over a 5-year time frame was $38.1 million dollars and represents the upper limit value of additional information. Conclusion: The results of our analysis suggest treatment of refractory NSCLC using a pharmacogenomic test based on gene copy number has the potential to improve average QALYs at considerable additional costs. The large EVPI suggests that additional research in this area is likely warranted.