Background: The coronavirus disease MESHD 2019 (COVID-19) causing a cluster of respiratory infections MESHD in Wuhan, China, is identified in December 2019. The main symptoms are defined as fever MESHD fever HP, cough MESHD cough HP, shortness of breath, with early symptom of sputum, acute respiratory distress HP syndrome MESHD (ARDS), and the final lung injury MESHD and pulmonary fibrosis MESHD pulmonary fibrosis HP. Currently, there is no effective method to cure it. Mesenchymal stem cell (MSC) therapy is an immediate need for treating COVID-19 especially severe patients at present.Methods: We describe the two confirmed case TRANS of COVID-19 severe patients in Hangzhou, China to explore the role of menstrual blood SERO-derived MSC in the treatment of SARS-CoV-2 infection MESHD. Furthermore, we mimic disease MESHD model of pulmonary fibrosis MESHD pulmonary fibrosis HP in mice to assess the role of MSC. Then, a co-culture system to investigate the underlying mechanism between MSC and pulmonary-associated cells by a series of Physiological, biochemical, bioinformatics analysis.Results: MSC transplantation increases the immune indicators (including lymphocytes) and decreases inflammatory indicators (such as IL-6, IL-10, TNF, and IFN). More importantly, the two patients alleviated symptom and discharged after 3 weeks’ treatment with MSC. Additionally, MSCs exhibit an anti-inflammatory role through suppressing some inflammatory factors (RANTES, GM-CSF, MIG-1g, MCP-5, Eotaxin), which is anastomotic to current clinical study using MSC to treat COVID-19. Conclusions: This is the first report using menstrual blood SERO-derived MSC in treating COVID-19 patients. From our clinical results, we hold one idea that MSCs reduced inflammatory effect to defend cytokine storm. The underlying mechanism is probably that MSCs inhibit epithelia cell apoptosis and reduce the secretion of inflammatory factors to prevent myofibroblasts activity. MSC provides an alternative method for treating COVID-19 particularly some patients with ARDS or subsequent pulmonary fibrosis MESHD pulmonary fibrosis HP.Trial registration: This clinical trial was submitted to and approved by the Ethics Committee of the First Affiliated Hospital, Collage of Medicine, Zhejiang University. MSC administration in patient with COVID-19 was conducted in a single center and open-label clinical trial (ChiCTR2000029606).