Dear Editor, Alveolar regeneration after an acute lung injury has been observed in many mammals. Results in animal models have shown that alveolar type II (AT2) cells function as resident alveolar stem cells that can proliferate and differentiate into alveolar type I (AT1) cells to build new alveoli after lung injury. 1 However, alveolar regeneration after acute lung injury in adult humans is still poorly characterized, mainly due to the lack of lung samples and regeneration-specific molecular markers. In patients with COVID-19 pneumonia, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can directly attack alveolar epithelial cells and cause massive AT2 cell death. It is unknown whether alveolar regeneration occurs upon SARS-CoV-2 infection-induced lung injury. This knowledge will substantially improve our basic understanding of the COVID-19 disease and our ability to prognosticate patient outcomes. In this study, we enrolled two COVID-19 patients. Patient-1 is a 58-year-old male and patient-2 is a 54-year-old male. Prior to the SARS-CoV-2 infection, both patients did not have signs of lung disorders. In the course of the disease, noninvasive ventilation, intubation, invasive ventilation, and extracorporeal membrane oxygenation (ECMO) were used in succession (Supplementary information, Fig. S1a, b). 2 An emergency lung transplant was performed on patient-1 on disease onset day 38 due to hemorrhage in his lungs (Supplementary information, Fig. S1a). The patient-2 received lung transplants on disease onset day 90 due to extensive pulmonary fibrosis (Supplementary information, Fig. S1b). Hematoxylin and eosin (H&E) staining of the lung specimen from both patients revealed that multiple cell aggregates were still evident in the alveolar lumen, indicating severe diffuse alveolar damage (Fig. 1 a). Immunostaining showed signs of lung fibrotic changes, including significant collagen I deposition and proliferating α-SMA+ myofibroblasts (Supplementary information, Fig. S2a, b). In most regions of the lungs of both patients, very few HTI-56+ AT1 cells were observed, indicating a significant depletion of AT1 cells (Fig. 1 b). Notably, we observed that alveolar regions harbored a large number of clustered AT2 cells lining the alveolar epithelium in patients’ lungs (Fig. 1 b). About 1.1% of AT2 cells in the lung of patient-1 and 10% of AT2 cells in the lung of patient-2 stained positive for Ki67, indicating that AT2 cells are proliferating (Fig. 1 b). Both phosphohistone H3 and PCNA staining results also indicate the increased proliferation of AT2 cells (Supplementary information, Fig. S3a, b). Together, these findings establish that AT2 cells are able to replicate additional AT2 cells after SARS-CoV-2-induced lung injury. Previous studies in both human and mouse lungs have confirmed the existence of a transient intermediate cell state for AT2 cells which occurs during differentiation of AT2 cells into AT1 cells. 3–7 AT2 cells in this intermediate cell state subsequently differentiate into AT1 cells. Three markers with transient expression profiles, Claudin4 (CLDN4), Stratifin (SFN), and Keratin 8 (KRT8), are known to specifically define this intermediate AT2 cell state. Few AT2 cells in the healthy donor lung expressed any of these markers. In contrast, many HTII-280+ AT2 cells in the COVID-19 lungs expressed CLDN4, SFN, or KRT8 (Fig. 1 c–e). Some AT2 cells that express CLDN4, SFN, or KRT8 show decreased expression levels of HTII-280 and proSPC