ImportanceCOVID-19 has severely impacted older populations and strained healthcare resources, with many patients requiring long periods of hospitalization. Reducing the hospital length of stay (LOS) reduces patient and hospital burden. Given that adverse drug reactions are known to prolong LOS, unmanaged pharmacogenomic risk and drug interactions among COVID-19 patients may be a risk factor for longer hospital stays.ObjectiveThe objective of this study was to determine if pharmacogenomic and drug interaction risks were associated with longer lengths of stay among high-risk patients hospitalized with COVID-19.DesignRetrospective cohort study of medical and pharmacy claimsSettingAdministrative database from a large U.S. health insurance companyParticipantsMedicare Advantage members with a first COVID-19 hospitalization between January 2020 and June 2020, who did not die during the stay.Exposures(1) Pharmacogenetic interaction probability (PIP) of ≤25% (low), 26%–50% (moderate), or >50% (high), which indicate the likelihood that one or more clinically actionable gene-drug or gene-drug-drug interactions would be identified with testing; (2) drug-drug interaction (DDI) severity of minimal, minor, moderate, major, or contraindicated, which indicate the severity of an interaction between two or more active medications.Main Outcomes and MeasuresThe primary outcome was hospital length of stay. Results were stratified by hierarchical condition categories (HCC) counts and chronic conditions.ResultsA total of 6,025 patients hospitalized with COVID-19 were included in the study. Patients with moderate or high PIP were hospitalized for 9% (CI: 4%–15%; p < 0.001) and 16% longer (CI: 8%–24%; p < 0.001), respectively, compared to those with low PIP, whereas RAF score was not associated with LOS. High PIP was significantly associated with 12%–22% longer lengths of stay compared to low PIP in patients with hypertension, hyperlipidemia, diabetes, or COPD. Finally, among patients with 2 or 3 HCCs, a 10% longer length of stay was observed among patients with moderate or more severe DDI compared to minimal or minor DDI.Conclusions and RelevanceProactively mitigating pharmacogenomic risk has the potential to reduce length of stay in patients hospitalized with COVID-19 especially those with COPD, diabetes, hyperlipidemia, and hypertension.Key PointsQuestionWhat is the impact of unmanaged pharmacogenomic risk among patients hospitalized with COVID-19?FindingsAmong 6,025 patients hospitalized with COVID-19, those with greater unmanaged pharmacogenomic risk for adverse drug reactions had longer hospital stays than those with lower risk, both within the entire cohort and within groups matched by number and type of chronic conditions.MeaningPreemptive pharmacogenomic testing may shorten hospital stay by reducing adverse drug reactions among seriously ill patients and more broadly improve patient risk classification, care utilization predictions, and health system performance.