Background: Patient-reported outcome measures (PROMs) can provide data on the barriers and facilitators of adherence to daily oral antiretroviral therapy (OART) regimens. We aimed to develop PROMs to understand perspectives of people with HIV (PWH) on: (1) facilitators/barriers to daily OART regimen adherence; and (2) a hypothetical switch to a long-acting (LA)-OART regimen. Methods: Following US FDA PRO guidance, targeted literature reviews (TLRs) and concept elicitation interviews with clinicians (n = 7) and PWH (n = 28) were conducted to develop conceptual models (CMs) of facilitators/barriers to OART regimen adherence. Three de novo PROMs were developed after an item-generation meeting (IGM). Three waves of cognitive debriefing (CD) interviews were conducted among PWH (n = 30) to demonstrate content validity and refine the PROMs. Results: The TLR identified 25 facilitators/barriers; a further 16 were added by clinicians and PWH and represented in 2 CMs. During the IGM, the CMs were used to develop 3 de novo PROMs: (1) HIV Patient Perspective of Regimen (HIV-PP-R); (2) HIV Patient Perspective of Regimen Change (HIV-PP-RC); and (3) HIV Drivers of Adherence Questionnaire (HIV-DAQ). In the CD interviews, PWH corroborated the relevancy of items in the PROMs, and minor adjustments were made for clarity. Conclusion: Three content-valid PROMs were developed to understand treatment experience of PWH taking daily OART and how that experience may be altered upon a switch to weekly LA-OART. Data from future LA-OART clinical trials will help define a scoring guide and evaluate the structure and measurement properties of the PROMs.