question: Background. Innate lymphoid cells (ILCs) are involved in immunity and homeostasis but, except for natural killer (NK) cells, their role in human viral infections is not well known. Puumala virus (PUUV) is a hantavirus that causes the acute zoonotic disease hemorrhagic fever with renal syndrome (HFRS). HFRS is characterized by strong systemic inflammation and NK cells are highly activated in HFRS, suggesting that also other ILCs might be responding to infection. Methods. Here we phenotypically analyzed peripheral ILCs in acute and convalescent PUUV-infected HFRS patients. Additionally, plasma levels of soluble factors and viral load were analyzed. Findings. Overall, the frequencies of NK cells and naive ILCs were reduced while the frequency of ILC2, in particular the ILC2-lineage committed c-Kitlo ILC2 subset, was increased during acute HFRS. Interestingly, we observed a negative correlation between viral load and frequencies of both NK and non-NK ILCs in acute HFRS. Phenotypically, ILCs displayed an activated profile with increased proliferation, and showed altered expression of several homing markers during acute HFRS. In line with the observation of activated ILCs, plasma levels of inflammatory proteins, including the ILC-associated cytokines interleukin (IL)-13, IL-23, IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), were elevated during acute HFRS. Interpretation. These findings indicate a general involvement of ILCs in response to human hantavirus infection. Further, this constitutes the first comprehensive study of ILCs in a hantavirus-caused disease, aiding in further understanding the role of these cells in disease pathogenesis and in human viral infections in general. Funding. A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.