Despite its promise for HIV prevention, the uptake of pre-exposure prophylaxis (PrEP) has been slow, and there have been substantial inequities in PrEP access. Young men who have sex with men and transgender women of color are most in need of PrEP and least likely to have that need fulfilled. PrEP telehealth care, which provides remote PrEP care via electronic communication, seems well suited to address several of the challenges of PrEP provision, including discomfort with stigmatizing and difficult-to-access health care systems, transportation challenges, and privacy concerns, and address disparities in PrEP access. Research suggests that PrEP telehealth care has promise and is a favored option for many prospective recipients of PrEP. However, despite growing attention to telehealth approaches as an avenue for increasing access to PrEP amidst the COVID-19 pandemic, there have been no published randomized controlled trials (RCTs) on PrEP telehealth care to date, making it difficult to draw strong conclusions about the advantages or disadvantages of telehealth compared with usual PrEP care. We developed PrEPTECH, a telehealth intervention that focuses specifically on alleviating issues of stigma, access, cost, and confidentiality for young people with risk factors for HIV infection who are seeking PrEP care. Leveraging data from the 2017 observational pilot study, we redesigned and enhanced PrEPTECH. This study aims to assess the effectiveness, acceptability, and feasibility of a telehealth HIV PrEP care intervention, PrEPTECH, in increasing PrEP uptake. This is the protocol for an RCT of young cisgender men and transgender women who have sex with men in 4 regions within the United States: the San Francisco Bay Area, California; Los Angeles County, California; Miami-Dade County, Florida; and Broward County, Florida. Participants in the intervention arm received access to a web-based telehealth program, PrEPTECH, which offers a fully web-based pathway to PrEP, whereas those in the control arm received access to a dynamic web page containing publicly available informational resources about PrEP. Follow-up data collection occurred at 3 and 6 months. An analysis will be conducted on outcomes, including PrEP initiation, persistence, adherence, coverage, and medication prescription, as well as PrEPTECH acceptability and feasibility. The study was funded in 2019 and received institutional review board approval in 2020. The PrEPTECH intervention was developed over the next 1.5 years. Study recruitment was launched in February 2022 and completed in September 2022, with 229 participants recruited in total. Data collection was completed in April 2023. The results of this RCT will offer valuable evidence regarding the effectiveness, acceptability, and feasibility of telehealth HIV PrEP care interventions among young cisgender men and transgender women who have sex with men. ClinicalTrials.gov NCT04902820; https://clinicaltrials.gov/ct2/show/NCT04902820. PRR1-10.2196/47932.