BACKGROUND: Patient portal use has been associated with improved patient health and improved adherence to medications, including statins. However, there is limited research on the association between patient portal registration and outcomes such as statin prescription refill adherence in the context of the National Health Service of England, where patient portals have been widely available since 2015. OBJECTIVE: We aimed to explore statin prescription refill adherence among general practice patients in England. METHODS: This study was approved by the Clinical Practice Research Datalink Independent Scientific Advisory Committee (ID: 21_000411). We used patient-level general practice data from the Clinical Practice Research Datalink in England. The data included patients with cardiovascular disease, diabetes, and chronic kidney disease, who were registered on the patient portal. The primary aim was to investigate whether statin prescription refill adherence, defined as ≥80% adherence based on the medication possession ratio, improved after patient portal registration. We used a multilevel logistic regression model to compare aggregate adherence 12 months before and 12 months after patient portal registration. RESULTS: We included 44,141 patients in the study. The analysis revealed a 16% reduction in the odds of prescription refill adherence 12 months after patient portal registration (odds ratio [OR]: 0.84, 95% CI 0.81-0.86) compared to 12 months before registration in the fully adjusted model for patient- and practice-level variables. CONCLUSIONS: This study evaluated prescription refill adherence after patient portal registration. Registering to the portal does not fully explain the mechanisms underlying the relationship between patient portal use and health-related outcomes such as medication adherence. Although a small reduction in prescription refill adherence was observed, this reduction disappeared when the follow up time was reduced to 6 months. Given the limitations of the study, reduction in prescription refill adherence cannot be entirely attributable to patient portal registration. However, there may be potential confounding factors influencing this association which should be explored through future research.