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Introduction: Oral P2Y12 inhibitor (P2Y12i) therapy remains a cornerstone in cardiovascular, vascular, and neurovascular care. However, significant interpatient variability in pharmacodynamic and pharmacokinetic response to therapy exists. Platelet reactivity testing with VerifyNow measures P2Y12 reaction units (PRU) which may inform decisions to adjust dosing or change P2Y12i agents. However, routine PRU monitoring is not recommended by guidelines and standard adjustment protocols are lacking. Inconsistencies in interpretation and/or therapy changes of P2Y12i based on PRU value may lead to increased thrombotic risk, bleeding risks, or adherence barriers. This study describes outcomes following inpatient PRU monitoring. Methods: This descriptive, retrospective study included patients receiving P2Y12i with ≥1 inpatient PRU test performed (July 2022–June 2024). Patients with PRU monitoring for periprocedural bleeding risk stratification were excluded. The primary endpoint was rate of therapy adjustments in the responder (PRU < 194) vs. non-responder group (PRU ≥194). Secondary endpoints included major adverse cardiovascular events (MACE), stent thrombosis, bleeding within 12 months, and analysis of patients with multiple PRU measurements. Results: Of 86 patients included, 51 (59.3%) were classified as responders and 35 (40.7%) as non-responders. Neurovascular intracranial stenosis with stent placement was the most common indication for P2Y12i therapy (37.2%). Significantly more therapy changes occurred in non-responders (65.7%) vs. responders (27.5%), p < 0.001. Among patients with safety data available, 9 experienced MACE (5 responders, 4 non-responders), 6 had stent thrombosis (3 responders, 3 non-responders), and 7 had bleeding events within 12 months (3 responders, 4 non-responders). Multiple PRU measurements were obtained in 32 of 86 patients (37.2%), with 16 (50%) undergoing therapy adjustments based on these results. Conclusions: P2Y12i non-responders were more likely to undergo therapy changes compared to responders. However, inconsistent therapy adjustment practices existed within the cohort, highlighting the need to standardize PRU monitoring and test interpretation for P2Y12i therapy in an inpatient setting.