OBJECTIVES: To estimate the clinical and economic trade-offs involved in using the molecular assay EPICUP to aid in identifying the primary site in Cancer of Unknown Primary (CUP). METHODS: A decision-analytic model was developed to estimate the lifetime clinical and economic outcomes of incorporating the EPICUP assay compared with other molecular assays (CancerTYPE ID, Cancer Origin Test and ResponseDX: Tissue of Origin Test). The analysis was limited to 6 primary cancer sites (breast, colon, pancreas, lung, liver and prostate) for adenocarcinoma histological subtype. Results are presented as incremental cost-effectiveness ratio (ICER, cost per quality-adjusted life-years [QALY] gained) from the USA Health Payers perspective. Model inputs were based on a case-control study of EPICUP, published literature, Surveillance Epidemiology and End Results database and a clinical expert panel. RESULTS: Based on a price of USD3,500 for EPICUP and for a willingness to pay USD100,000, EPICUP is cost-effective (vs. CancerTYPE ID, Cancer Origin Test and ResponseDX: Tissue of Origin Test) in all tumors analyzed, ranging between 80% and 100% of the simulations. EPICUP increased the proportion of patients treated correctly, decreased the proportion of patients treated with an empiric approach, and increased the quality-adjusted overall survival. For a willingness to pay USD50,000 EPICUP is cost-effective in breast, colon, pancreas, lung (NSCLC) and prostate cancer, again ranging between 80% and 100% of the simulations. These findings were robust across deterministic and probabilistic sensitivity analyses. CONCLUSIONS: EPICUP assay for diagnosing the primary tumor in CUP patients is a cost-effective approach in breast, colon, pancreas, lung (NSCLC), hepatocellular and prostate cancer in comparison with other alternatives available, while improving patient care.