Introduction: Real-world evidence that compares the treatment patterns of targeted long-term prophylaxis (LTP) for hereditary angioedema (HAE), including berotralstat, lanadelumab, and subcutaneous (SC) plasma-derived C1 inhibitor (pdC1-INH) is limited. Objective: The study aimed to assess adherence and persistence after initiation of berotralstat, lanadelumab, or SC-pdC1-INH. Methods: Electronic health records linked to claims data was used to select patients ages ≥ 12 years, initiating one of three LTPs between June 22, 2017, and September 12, 2023, with mutually exclusive cohorts assigned hierarchically in reverse order of their U.S. Food and Drug Administration approval date. Patients were required to have ≥ 12 months of continuous enrollment before and after the LTP initiation date. Demographics and baseline clinical characteristics were captured. Primary study measures were adherence, defined as the mean proportion of days covered (PDC), and persistence, defined as having no gap in treatment ≥ 45 days after the LTP initiation date. A subgroup analysis was conducted among patients with two or more claims for their index LTP. A sensitivity analysis was performed by reassigning cohorts based on the first claim for qualifying LTP after June 22, 2017. Results: The main analysis included 357 patients (90 on berotralstat, 189 lanadelumab, and 78 SC-pdC1-INH). Overall, 46% to 51% of the patients had LTP experience. Adherence (mean PDC) was similar between treatments at 0.73, 0.78, and 0.74 for berotralstat, lanadelumab, and SC-pdC1-INH, respectively. Proportions of patients persistent on index LTP after 12 months were similar across LTPs: 61%, 58%, and 53% for berotralstat, lanadelumab, and SC-pdC1-INH, respectively. The findings of the subgroup and sensitivity analyses supported the main analysis. Conclusion: Adherence and persistence rates for all three LTP treatments were uniformly high. Berotralstat adherence and persistence were comparable with those observed after lanadelumab or SC-pdC1-INH initiation in the main analysis, among patients with two or more claims for their index LTP, and among cohorts assigned based on the first claim for qualifying LTP.