Plasma metagenomic sequencing (pmNGS) is an infectious disease diagnostic tool that detects microbial DNA from patient plasma¹. Due to its unbiased nature, pmNGS can identify bacteria, fungi, parasites and DNA viruses, including those clinicians may have not considered in their differential diagnosis or that are difficult to identify via standard testing². The diagnostic power of pmNGS can circumvent invasive and expensive diagnostic procedures³ and, potentially, shorten patient stays. However, the per-syndrome utility of pmNGS is not well established, and its cost is relatively high compared to other infectious disease diagnostics. Absent institutional or national guidelines for test use, UCSF has seen skyrocketing volumes of pmNGS, with an increase from 18 tests in 2018 to 616 tests in 2024, with an estimated annual cost of ~$1 million. Here we propose a multipronged approach to define the clinical indications for which pmNGS has highest impact, reduce costs of unnecessary testing, analyze hospital days saved, avoid costs related to procedures, and promote equity and excellence. We have created an Infectious Disease/Clinical Microbiology Consensus Molecular Testing Guidance to guide use of pmNGS testing at UCSF (Appendices 1-2). We will update the APeX lab order for pmNGS to align with this guidance. Next, we will estimate pmNGS effects on patient antimicrobial management, length of stay, and need for procedures, stratified by clinical syndrome (Appendix 3). This approach will enable assessment of pmNGS utility, improve care, and reduce waste.