OBJECTIVES: Liquid biopsy (LBx) somatic mutation panels are being explored by many pharmaceutical companies as a companion diagnostic strategy to evaluate biomarker status and determine eligibility for oncology therapies. This study aimed to evaluate the current US payer coverage landscape and understand payers’ perceptions of LBx somatic mutation panels. METHODS: We conducted secondary research on US payer policies to determine current coverage of LBx panels. We also conducted qualitative interviews with US payers to evaluate awareness and perception of LBx. RESULTS: Medicare covers FDA-approved LBx next-generation sequencing (NGS) panels for eligible beneficiaries with advanced cancer following a National Coverage Determination issued in March 2018. Further coverage opportunities for non-FDA-approved LBx-based NGS panels exist at a local Medicare Administrative Contractor level. Medicaid coverage is difficult to discern based on the lack of publicly available information—among States covering NGS-based panels, none explicitly cover nor deny LBx-based panels. Commercial coverage is fragmented and few commercial payer policies explicitly cover LBx-based panels. Additionally, payers acknowledge the difficulty of delineating between liquid vs. tissue specimen type through existing CPT coding and billing procedures, so LBx panels may be covered “under the radar” in some instances. Payers have a favorable impression of liquid biopsy, noting the non-invasive nature of the tests and the ability to overcome tumor heterogeneity. Accuracy and concordance to tissue, as well as price remain the top concerns. The desire for robust LBx clinical validity and clinical utility evidence is expressed. CONCLUSIONS: Differential access to LBx somatic mutation panels exists across US beneficiary populations, which can pose an access challenge for oncology drugs associated with such a companion diagnostic strategy. To encourage more widespread commercial payer coverage, companies should demonstrate LBx panel accuracy and present a concrete value story.