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Background  Despite numerous advances in the identification of risk factors for the development of severe coronavirus disease 2019 (COVID-19), factors that promote recovery from COVID-19 remain unknown. Natural killer (NK) cells provide innate immune defense against viral infections and are known to be activated during moderate and severe COVID-19. Killer immunoglobulin-like receptors (KIR) mediate NK cell cytotoxicity through recognition of an altered MHC-I expression on infected target cells. However, the influence of KIR genotype on outcome of patients with COVID-19 has not been investigated so far. We retrospectively analyzed the outcome associations of NK cell count and KIR genotype of patients with COVID-19 related severe ARDS treated on our tertiary intensive care unit (ICU) between February and June 2020 and validated our findings in an independent validation cohort of patients with moderate COVID-19 admitted to our tertiary medical center.    Results  Median age of all patients in the discovery cohort ( n  = 16) was 61 years (range 50–71 years). All patients received invasive mechanical ventilation; 11 patients (68%) required extracorporeal membrane oxygenation (ECMO). Patients who recovered from COVID-19 had significantly higher median NK cell counts during the whole observational period compared to patients who died (121 cells/µL, range 16–602 cells/µL vs 81 cells/µL, range 6–227 cells/µL,  p -value = 0.01). KIR2DS5 positivity was significantly associated with shorter time to recovery (21.6 ± 2.8 days vs. 44.6 ± 2.2 days,  p -value = 0.01). KIR2DS5 positivity was significantly associated with freedom from transfer to ICU (0% vs 9%,  p -value = 0.04) in the validation cohort which consisted of 65 patients with moderate COVID-19.    Conclusion  NK cells and KIR genotype might have an impact on recovery from COVID-19.    Supplementary Information  The online version contains supplementary material available at 10.1186/s40635-021-00409-4.

Killer immunoglobulin-like receptor 2DS5 is associated with recovery from coronavirus disease 2019