Background Many countries and organizations recommended people living with HIV/AIDS (PLWHA) receive the COVID-19 vaccine. However, vaccine hesitancy still exists and becomes a barrier for promoting COVID-19 vaccination among PLWHA. Objective This study aims to investigate factors that contributed to COVID-19 vaccine hesitancy among PLWHA. Methods The study used a multicenter cross-sectional design and an online survey mode. We recruited PLWHA aged 18-65 years from 5 metropolitan cities in China between January 2021 and February 2021. Participants completed an online survey through Golden Data, a widely used encrypted web-based survey platform. Multiple linear regression models were used to assess the background characteristics in relation to COVID-19 vaccine hesitancy, and structural equation modeling was performed to assess the relationships among perceived benefits, perceived risks, self-efficacy, subjective norms, and COVID-19 vaccine hesitancy. Results Among 1735 participants, 41.61% (722/1735) reported COVID-19 vaccine hesitancy. Older age, no other vaccinations in the past 3 years, and having chronic disease history were positively associated with COVID-19 vaccine hesitancy. Structural equation modeling revealed a direct relationship of perceived benefits, perceived risks, and subjective norms with self-efficacy and vaccine hesitancy and an indirect relationship of perceived benefits, perceived risks, and subjective norms with vaccine hesitancy. Moreover, self-efficacy toward COVID-19 vaccination was low. PLWHA had concerns of HIV disclosure during COVID-19 vaccination. Family member support could have an impact on COVID-19 vaccination decision-making. Conclusions COVID-19 vaccine hesitancy was high among PLWHA in China. To reduce COVID-19 vaccine hesitancy, programs and strategies should be adopted to eliminate the concerns for COVID-19 vaccination, disseminate accurate information on the safety and efficacy of the COVID-19 vaccine, encourage family member support for COVID-19 vaccination, and improve PLWHA’s trust of medical professionals.