HIV Pre-Exposure Prophylaxis (PrEP) has been available in Wales since 2017. The coronavirus disease (COVID-19) pandemic impacted UK sexual health services, leading to a reduction in service provision. There is a lack of research on the experiences of PrEP users during this time. We aimed to explore the experiences of PrEP users in Wales following the introduction of COVID-19 pandemic measures. We conducted a secondary data analysis of two prior interview studies (DO-PrEP and UPrEP). Data collection was undertaken between May 2020 and February 2021 using remote interviewing. Semi-structured interviews were conducted. Participants were ≥18 years of age, residents of Wales, current or previous PrEP users, and men who have sex with men (MSM). Reflexive thematic analysis was conducted. A total of 32 interviews were included in the analysis. Themes include the following: (1) PrEP use during COVID-19, (2) sexual behaviour and relationship changes following COVID-19 restrictions, (3) NHS service provision during the COVID-19 pandemic, and (4) wider contextual effects of the pandemic. Participants reported a change in PrEP use (pausing or switching to event-based PrEP). Participants reported reduced access to clinics and appointments. Support for changing to event-based PrEP was varied. Social isolation resulted in varied responses to lockdown rules, especially in later lockdowns. This study provides patient perspectives on the challenges the COVID-19 pandemic posed to PrEP use and access. It offers insights into the broader support needs around PrEP use when an individual's circumstances change. Flexible models of PrEP provision, which can be adapted to the patient's needs, will be essential as PrEP delivery extends into the wider community. Both the DO-PrEP and UPrEP studies received input from various stakeholders in the design of the topic guides for the study; these included public lay members, PrEP users, PrEP providers, and individuals involved with HIV advocacy and policy.