ImportanceNew-onset retinal vascular occlusion (RVO) occurring acutely after messenger RNA (mRNA) COVID-19 vaccination has been described in recent literature. Because RVO can cause vision loss or blindness, an epidemiologic investigation evaluating this potential association is of great importance to public health.ObjectiveTo investigate how often patients are diagnosed with new RVO acutely after the mRNA COVID-19 vaccine compared with influenza and tetanus, diphtheria, pertussis (Tdap) vaccines.Design, Setting, and ParticipantsA retrospective population-based cohort design using the TriNetX Analytics platform, a federated, aggregated electronic health record (EHR) research network containing the deidentified EHR data of more than 103 million patients, was used to examine aggregate EHR data. Data were collected and analyzed on October 20, 2022. Data on patients within the TriNetX Analytics platform were searched for the presence of vaccination Common Procedural Technology codes, and instances of newly diagnosed RVO within 21 days of vaccination were recorded and reported. Propensity score matching based on demographic characteristics (age, sex, race and ethnicity) and comorbidities (diabetes, hypertension, and hyperlipidemia) was performed between vaccination groups for evaluation of relative risks (RRs).Main Outcomes and MeasuresThe appearance of a new-encounter diagnosis of RVO within 21 days of the mRNA COVID-19 vaccination was the primary outcome. Historical comparison cohorts of patients receiving influenza and Tdap vaccinations allowed for evaluation of the RRs for RVO.ResultsOf 3 108 829 patients (mean [SD] age at vaccination, 50.7 [20.4] years; 56.4% women) who received the mRNA COVID-19 vaccine, 104 (0.003%; 95% CI, 0.003%-0.004%) patients had a new diagnosis of RVO within 21 days of vaccination. After propensity score matching, the RR for new RVO diagnosis after the first dose of COVID-19 vaccination was not significantly different from that after influenza (RR, 0.74; 95% CI, 0.54-1.01) or Tdap (RR, 0.78; 95% CI, 0.44-1.38) vaccinations, but was greater when compared with the second dose of the COVID-19 vaccination (RR, 2.25; 95% CI, 1.33-3.81).Conclusions and RelevanceThe findings of this study suggest that RVO diagnosed acutely after mRNA COVID-19 vaccination occurs extremely rarely at rates similar to those of 2 different historically used vaccinations, the influenza and Tdap vaccines. No evidence suggesting an association between the mRNA COVID-19 vaccination and newly diagnosed RVO was found.