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Background Despite the disproportionate morbidity and mortality experienced by American Indian and Alaska Native (AI/AN) persons during the COVID-19 pandemic, few studies have reported vaccine effectiveness (VE) estimates among these communities. Methods We conducted a test-negative case-control analysis among AI/AN persons aged ≥12 years presenting for care from January 1, 2021 through November 30, 2021 to evaluate effectiveness of mRNA COVID-19 vaccines against COVID-19-associated outpatient visits and hospitalizations. Cases and controls were patients with ≥1 symptom consistent with COVID-19-like illness; cases were defined as those test-positive for SARS-CoV-2 and controls were defined as those test-negative for SARS-CoV-2. We used unconditional multivariable logistic regression to estimate VE, defined as 1 minus the adjusted odds ratio for vaccination among cases versus controls. Results The analysis included 207 cases and 267 test-negative controls. Forty-four percent of cases and 78% of controls received two doses of either BNT162b2 or mRNA-1273 vaccine. VE point estimates for two doses of mRNA vaccine were higher for hospitalized participants (94.6% [88.0–97.6]) than outpatient participants (86.5% [63.0–95.0]), but confidence intervals overlapped. Conclusions Among AI/AN persons, mRNA COVID-19 vaccines were highly effective in preventing COVID-associated outpatient visits and hospitalizations. Maintaining high vaccine coverage, including booster doses, will reduce the burden of disease in this population.

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