OBJECTIVES: Population-wide screening for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements to inform cancer therapy in non-small cell lung cancer (NSCLC) is recommended by guidelines.  We estimated cost-effectiveness of multiplexed predictive biomarker screening in metastatic NSCLC from a societal perspective in the US. METHODS: We constructed a microsimulation model to compare the life expectancy and costs of multiplexed testing and molecularly guided therapy vs treatment with cisplatin-pemetrexed (CisPem).  All testing interventions included a two-step algorithm of concurrent EGFR mutation and ALK overexpression testing with immunohistochemistry (IHC) followed by ALK rearrangement confirmation with a fluorescence in situ hybridization (FISH) assay for IHC positive results.  Three strategies were included:  ‘Test-treat’ approach, where molecularly guided therapy was initiated after obtainment of test results; ‘Empiric switch therapy’, with concurrent initiation of CisPem and testing and immediate switch to test-result conditional treatment after one cycle of CisPem; and ‘Empiric therapy’ approach in which CisPem was continued for four cycles before start of a tyrosine kinase inhibitor (TKI).   RESULTS: The incremental cost-effectiveness ratio (ICER) for ‘Test-treat’ compared to treatment with CisPem was $136,000 per quality-adjusted life year (QALY) gained.  Both empiric treatment approaches had less favorable ICERs.  ‘Test-treat’ and ‘Empiric switch therapy’ yielded higher expected outcomes in terms of QALYs and life-years (LYs) than ‘Empiric therapy’.  These results were robust across plausible ranges of model inputs. CONCLUSIONS: From a societal perspective, our cost-effectiveness results support the value of multiplexed genetic screening and molecularly guided therapy in metastatic NSCLC.