Background: Pharmacy administrative claims data remain an accessible and efficient source to measure medication adherence for frequently hospitalized patient populations that are systematically excluded from the landmark drug trials. Published pharmacotherapy studies use medication possession ratio (MPR) and proportion of days covered (PDC) to calculate medication adherence and usually fail to incorporate hospitalization and prescription overlap/gap from claims data. To make the cacophony of adherence measures clearer, this study created a refined hospital-adjusted algorithm to capture pharmacotherapy adherence among patients with end-stage renal disease (ESRD). Methods: The United States Renal Data System (USRDS) registry of ESRD was used to determine prescription-filling patterns of those receiving new prescriptions for oral P2Y12 inhibitors (P2Y12-I) between 2011 and 2015. P2Y12-I-naïve patients were followed until death, kidney transplantation, discontinuing medications, or loss to follow-up. After flagging/censoring key variables, the algorithm adjusted for hospital length of stay (LOS) and medication overlap. Hospital-adjusted medication adherence (HA-PDC) was calculated and compared with traditional MPR and PDC methods. Analyses were performed with SAS software. Results: Hospitalization occurred for 78% of the cohort (N = 46 514). The median LOS was 12 (interquartile range [IQR] = 2-34) days. MPR and PDC were 61% (IQR = 29%-94%) and 59% (IQR = 31%-93%), respectively. After applying adjustments for overlapping coverage days and hospital stays independently, HA-PDC adherence values changed in 41% and 52.7% of the cohort, respectively. When adjustments for overlap and hospital stay were made concurrently, HA-PDC adherence values changed in 68% of the cohort by 5.8% (HA-PDC median = 0.68, IQR = 0.31-0.93). HA-PDC declined over time (3M-6M-9M-12M). Nearly 48% of the cohort had a ≥30 days refill gap in the first 3 months, and this increased over time ( P < .0001). Conclusions: Refill gaps should be investigated carefully to capture accurate pharmacotherapy adherence. HA-PDC measures increased adherence substantially when adjustments for hospital stay and medication refill overlaps are made. Furthermore, if hospitalizations were ignored for medications that are included in Medicare quality measures, such as Medicare STAR program, the apparent reduction in adherence might be associated with lower quality and health plan reimbursement.