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Background Estimates of coronavirus disease 2019 (COVID-19) vaccine effectiveness under real-world conditions, and understanding of barriers to uptake, are necessary to inform vaccine rollout. Methods We enrolled cases (testing positive) and controls (testing negative) from among the population whose SARS-CoV-2 molecular diagnostic test results from 24 February to 29 April 2021 were reported to the California Department of Public Health. Participants were matched on age, sex, and geographic region. We assessed participants' self-reported history of mRNA-based COVID-19 vaccine receipt (BNT162b2 and mRNA-1273). Participants were considered fully vaccinated 2 weeks after second dose receipt. Among unvaccinated participants, we assessed willingness to receive vaccination. We measured vaccine effectiveness (VE) via the matched odds ratio of prior vaccination, comparing cases with controls. Results We enrolled 1023 eligible participants aged ≥18 years. Among 525 cases, 71 (13.5%) received BNT162b2 or mRNA-1273; 20 (3.8%) were fully vaccinated with either product. Among 498 controls, 185 (37.1%) received BNT162b2 or mRNA-1273; 86 (16.3%) were fully vaccinated with either product. Two weeks after second dose receipt, VE was 87.0% (95% confidence interval: 68.6–94.6%) and 86.2% (68.4-93.9%) for BNT162b2 and mRNA-1273, respectively. Fully vaccinated participants receiving either product experienced 91.3% (79.3–96.3%) and 68.3% (27.9–85.7%) VE against symptomatic and asymptomatic infection, respectively. Among unvaccinated participants, 42.4% (159/375) residing in rural regions and 23.8% (67/281) residing in urban regions reported hesitancy to receive COVID-19 vaccination. Conclusions Authorized mRNA-based vaccines are effective at reducing documented SARS-CoV-2 infections within the general population of California. Vaccine hesitancy presents a barrier to reaching coverage levels needed for herd immunity. [ABSTRACT FROM AUTHOR]