Background: Coronavirus disease 2019 (COVID-19) is a pandemic with no specific drugs and high fatality. The most urgent need is to find effective treatments. We sought to determine whether pirfenidone treatment might reduce the death risk of COVID-19 patients. Methods: Clinically confirmed COVID-19 cases at Tongji Hospital, Wuhan, China from January 29, 2020 and April 27, 2020 were identified from electronic medical records. Information on their demographics, history of coexisting diseases, and therapies during hospitalization were extracted. Based on whether taking pirfenidone during hospitalization, patients were categorized into non-pirfenidone group and pirfenidone group. The patients were further matched using propensity score analysis. Results: In this retrospective study, about 59 patients were treated by pirfenidone during hospitalization and 59 patients with non-pirfenidone were matched. Compared with patients without pirfenidone therapy, patients with pirfenidone therapy showed a better clinical outcome and a decreased mortality (1.7% [1/59] vs. 32.2% [19/59]; p<0.001). In terms of chest computed tomography (CT) images, the ground-glass opacity (GGO)/consolidation signs were obviously absorbed in the pirfenidone treated patients before discharge compared with patients on admission. Moreover, the level of interleukin (IL)-6 and IL-2 receptor were reduced on day 3 after pirfenidone treatment. Moreover, there was a trend that patients with pirfenidone therapy had lower levels of IL-1β, combined with lower hs-CRP, lymphocytes, LDH and NT-proBNP on day 3 after pirfenidone administration. In addition, patients with pirfenidone therapy had higher serum albumin level on day 3 after pirfenidone administration.Conclusion: COVID-19 patients could benefit from the pirfenidone therapy during hospitalization.