Persistent environmental contaminants accumulate in ecosystems and human bodies creating long-term health concerns - PFAS compounds resist degradation while bioaccumulating, making their presence in medical devices increasingly problematic under evolving regulations. PFAS (per- and polyfluoroalkyl substances) analysis by LC-MS/MS addresses these persistent environmental contaminants of increasing regulatory concern, with methodology targeting expanding lists of restricted PFAS compounds. The analytical approach achieves sub-ppb detection limits required for compliance with stringent regulations limiting these "forever chemicals" that persist in environment and bioaccumulate in organizms. Critical for devices with fluoropolymer components including PTFE tubing and coatings, demonstrating compliance with emerging PFAS regulations restricting these persistent compounds, and addressing stakeholder concerns about environmental persistence even when health effects remain uncertain. For medical devices, PFAS testing validates that fluoropolymer processing adequately removes manufacturing residues including perfluorooctanoic acid (PFOA) used in PTFE production, alternative materials replacing restricted PFAS don't introduce equally problematic fluorinated compounds, and device use doesn't release PFAS at levels triggering regulatory concerns. The LC-MS/MS methodology provides sensitive detection distinguishing individual PFAS compounds in complex mixtures, quantifies both legacy PFAS like PFOS and PFOA plus replacement compounds, and accommodates regulatory method updates as restricted compound lists expand. Manufacturing validation ensures processing removes PFAS contamination from equipment and materials, incoming material screening verifies supplier claims about PFAS-free status, and product testing demonstrates compliance with market-specific regulations varying by region. The analysis proves essential as regulations tighten globally with EU restrictions expanding, US EPA limits strengthening, and environmental advocacy increasing pressure for PFAS elimination from consumer and medical products.