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Abstract Background and objectivesThe optimal iron hypothesis (OIH) posits that risk for infection is lowest at a mild level of iron deficiency. The extent to which this protection results from arms race dynamics in the evolution of iron acquisition and sequestration mechanisms is unclear. We evaluated the OIH with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an emerging infectious agent. MethodologyWe tested 304 healthcare workers at baseline for iron deficiency (zinc protoporphyrin:heme), anemia (hemoglobin), and SARS-CoV-2 (salivary PCR), and followed them for ~3 months with biweekly SARS-CoV-2 tests. We fit logistic regression models based on Akaike Information Criterion. ResultsAdequate data were available for 199 participants. Iron replete (OR: 2.87, 95% CI: 0.85, 9.75) and anemia (OR: 2.48; 95% CI: 0.82, 7.85) were associated with higher risk for SARS-CoV-2 infection after control for covariates. Logistic regression and Cox proportional hazards models of the SARS-CoV-2 outcome were similar. Anemia (OR: 1.81; 95% CI: 0.88, 3.71) was associated with respiratory symptoms regardless of SARS-CoV-2 infection. Conclusions and implicationsThese findings provide partial support for the OIH: SARS-CoV-2 infection risk was elevated at the high end of the range of iron availability; however, the elevated risk among those with anemia was not, as expected, specific to severe iron deficiency. Narrowly, for COVID-19 epidemiology, these findings accord with evidence that SARS-CoV-2’s ability to establish infection is enhanced by access to iron. More broadly, these findings suggest that the OIH does not hinge on a long history of evolutionary arms race dynamics in access to host iron.