Background <p>Although concerns about the safety and efficacy of antiretroviral therapy (ART) for HIV infection have been largely resolved, new challenges—including maintaining adherence and persistence in the context of aging and comorbidities of people with HIV—are growing more important in many Asian countries, including Japan. We evaluated the association between concomitant pill number burden and adherence/persistence to ART single-tablet or multiple-tablet regimens (STR, MTR).</p> Methods <p>We conducted a retrospective cohort study using data from a Japanese national pharmacy dispensing claims database. The primary outcome was adherence, measured by proportion of days covered (PDC); good adherence was defined as PDC ≥ 90%, and persistence was defined by time to discontinuation.</p> Results <p>A total of 5,289 prescription episodes were analyzed, including 4,319 of first-line treatment. Concomitant pill burden of 1, 2, 3–4, or ≥ 5 did not result in significantly different odds of maintaining a PDC ≥ 90% in STR or MTR episodes, and PDC was not significantly different between STR and MTR for patients with different numbers of concomitant pill burden. Among MTR prescription episodes, patients aged 40–49, 50–59, or 60–69 years were more likely to have a PDC ≥ 90% vs. the reference group of patients aged 18–29 years. Overall, the persistence rate was greater with STR vs. MTR among patients with 0, 1, or 2 concomitant medications.</p> Conclusions <p>Although greater pill burden was not associated with differences in adherence vs. no concomitant pill burden, simplification of ART and consideration of concomitant treatments for comorbidities may contribute toward maintaining persistence. Use of STR may be particularly beneficial toward maintaining adherence in younger patients.</p> Clinical trial number <p>Not applicable.</p>