Background: Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Some epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutations make tumours responsive to treatment with EGFR-TK inhibitors (EGFR-TKIs) but less responsive to treatment with standard chemotherapy. Patients with NSCLC are therefore tested for EGFR-TK tumour gene mutations to inform treatment decisions. There are a variety of tests available to detect these mutations. The different tests vary in the specific mutations that they attempt to detect, the amount of tumour cells needed for the test to work, the time that it takes to give a result, the error rate of the test, and the cost of the test. Objective: To compare the performance and cost-effectiveness of EGFR-TK mutation tests used to identify previously untreated adults with locally advanced or metastatic NSCLC, who may benefit from first-line treatment with TKIs. Data sources: Twelve databases to August 2012 [including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations and Daily Update (OvidSP), EMBASE, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment database (HTA), Science Citation Index (SCI), Latin American and Caribbean Health Sciences Literature (LILACS), BIOSIS Previews, NIHR Health Technology Assessment programme, PROSPERO (International Prospective Register of Systematic Reviews)], research registers and conference proceedings. A web-based survey gathered data on technical performance of EGFR-TK mutation tests. Methods: Randomised controlled trials were assessed for methodological quality using the Cochrane risk of bias tool. Diagnostic accuracy studies were assessed using QUADAS-2. There were insufficient data for meta-analysis. For accuracy studies, we calculated sensitivity and specificity together with 95% confidence intervals (CIs). Survival data were summarised as hazard ratios and tumour response data as relative risks, with 95% CIs. The health-economic analysis considered the long-term costs and quality-adjusted life-years (QALYs) associated with different tests followed by treatment with either standard chemotherapy or a TKI. Direct sequencing was taken as the comparator. The de novo model consisted of a decision tree and a Markov model. Results: The survey indicated no differences between tests in batch size, turnaround time, number of failed samples or cost. Six studies provided data on the accuracy of EGFR-TK mutation testing for predicting response to treatment with TKIs. Estimates of accuracy were similar across studies. Six analyses provided data on the clinical effectiveness of TKIs compared with standard chemotherapy. There were no clear differences in the treatment effects reported by different studies, regardless of which EGFR mutation test was used to select patients. Cost-effectiveness analysis using 'Evidence on comparative effectiveness available' and 'Linked evidence' approaches: Therascreen (R) EGFR polymerase chain reaction (PCR) Kit (Qiagen, Venlo, the Netherlands) was both less effective and less costly than direct sequencing of all exon 19-21 mutations at an incremental cost-effectiveness ratio of 32,167 pound (comparative) and 32,190 pound (linked) per QALY lost. 'Assumption of equal prognostic value' approach: the lowest total strategy cost was [commercial-in-confidence (CiC) information has been removed] [Sanger sequencing or Roche cobas EGFR Mutation Testing Kit (R) (Roche Molecular Systems, Inc., Branchburg, NJ, USA)] compared with (CiC information has been removed) for the most expensive strategy (fragment length analysis combined with pyrosequencing). Limitations: The cost-effectiveness analysis assumed that the differences in outcomes between the results of the trials were solely attributable to the different mutation tests used to distinguish between patients; this assumption ignores other factors that might explain this variation. Conclusion: There was no strong evidence that any one EGFR mutation test had greater accuracy than any other test. Re-testing of stored samples from previous studies, where patient outcomes are already known, could be used to provide information on the relative effectiveness of TKIs and standard chemotherapy in patients with EGFR mutation-positive and mutation-negative tumours, where mutation status is determined using tests for which adequate data are currently unavailable.