Low levels and function of natural killer (NK) cells are associated with increased coronavirus disease 2019 (COVID-19) severity. NK cell immunotherapy may improve immune function to reduce infection severity. We conducted a first-in-human, open-label, phase 1, dose-escalating (100 × 10 ⁶ , 300 × 10 ⁶ , or 900 × 10 ⁶ cells) study of a single dose of DVX201, a cord-blood-derived allogeneic NK cell therapy, in hospitalized patients with COVID-19. Participants were followed for 28 days. The maximum allowed steroid dose for eligibility was up to 0.5 mg/kg prednisone (or equivalent) daily. We enrolled nine participants, 3 per dose level. Eight participants had ≥1 comorbidity associated with increased COVID-19 severity, three of whom had a hematologic malignancy. Infusions were well tolerated, with no treatment-related adverse events. There was no evidence of inflammatory complications related to infusions. Peripheral blood NK cells generally increased after infusion, peaking by day 7. The median time from infusion to discharge was 2 days (range: 1-13). Two patients (both with acute lymphoblastic leukemia) were readmitted with recurrent COVID-19. This trial demonstrates the safety of allogeneic NK cell immunotherapy as a potential antiviral. Larger controlled trials are needed to establish efficacy.