This report systematically reviewed the existing evidence on the cost-effectiveness of the EGFR mutation analysis. Our review found one preliminary cost-effectiveness study (a conference presentation), showing that the EGFR mutation analysis is cost-effective compared with no-testing strategy, if the society’s threshold for cost per additional progression-free survival year was US$17,184. However, the modeling structure was restrictive because (1) progression-free survival (not the overall survival) was the primary outcome, (2) impacts of therapies on HRQL were not considered, and (3) most importantly, treatment sequence was not modelled. Given the relatively early phase of the technological development of the EGFR mutation analysis, an economic framework was developed to provide guidance for analysts in conducting future cost-effectiveness analyses on the EGFR mutation analysis. Our economic modeling framework described comprehensive decision-analytic models to assess cost-effectiveness of EGFR mutation analysis to select first-line therapies for advanced NSCLC patients. The proposed framework reflects closely the CADTH economic guideline and the recently published CADTH oncology guidelines. With the accumulation of clinical evidence on the test validity and clinical utility of EGFR mutation analysis, analysts will be able to conduct formal cost-effectiveness analyses, which help guide future reimbursement decisions on EGFR mutation analysis.