Background <p>In the U.S., responses to the rollout of COVID-19 vaccine varied widely, with contrasting perceptions of the vaccine. We aimed to characterize distinct groups of respondents regarding COVID-19 vaccine perceptions.</p> Methods <p>Data came from the 2021–2023 Common Survey (<i>n</i> = 852), collected in Chicago using a community-based participatory approach focusing on communities with low COVID-19 vaccination. Participants answered eight questions about vaccine-related perceptions. We conducted a latent class analysis in R.</p> Results <p>The sample included 623 female participants (73.1%), 482 Black participants (56.6%), 259 Hispanic/Latino(a) participants (30.4%), 26 Asian participants (3.1%), and 261 participants with a college degree (30.6%). In a four-class model, Class 1 (skeptic) included 153 participants (18.0%) with low confidence in vaccine safety, effectiveness, and potential to get life back to normal. Class 2 (uncertain) included 163 participants (19.1%) who mostly indicated uncertainty. Class 3 (support with concerns) included 266 participants (31.2%) who recognized many vaccine benefits but also had concerns about its rapid development and “not being studied in people like me.” Class 4 (pro-vaccine) included 270 participants (31.7%) with high confidence in vaccine safety and effectiveness and social approval of vaccination. Interestingly, both the skeptic and pro-vaccine groups had somewhat similar agreement with the statement “not enough information on COVID vaccine interaction.” Class assignments varied by sociodemographic characteristics. Socioeconomic hardships were associated with a lower likelihood of being in the “pro-vaccine” group.</p> Conclusions <p>Given the distinct classes of vaccine beliefs, tailored public health messaging is needed to enhance vaccine confidence and uptake.</p>