Lymphopenia is common in respiratory viral infection. However, no studies elucidated the impact of prolonged lymphopenia on worse outcome in the way of quantitative risk.Adult patients with laboratory-confirmed respiratory virus infection (influenza, SARS-CoV-2, and other viruses) between January 1st, 2016, and February 1, 2023 were enrolled in this retrospective cohort study. Serial data of laboratory examination during hospitalization were acquired. The primary outcome was in-hospital all-cause death, and all information was obtained from the electronic medical records system. Legendre orthogonal polynomials (LOP), restricted cubic splines, and multivariable logistic regression were performed.Finally, 2388 inpatients were involved in this study, including 436 patients with influenza, 1397 with SARS-CoV-2, and 319 with other respiratory virus infections. After being adjusted for age, corticosteroids, chronic kidney disease, chronic respiratory disease, cardiovascular disease, lymphopenia on admission and length of hospital stay, prolonged lymphopenia was significantly associated with death in influenza (OR 7.20, 95 % CI 2.27-22.77, p = 0. 0008 for lasting for 3-7 days; OR 17.80, 95 % CI 5.21-60.82, p < 0.0001 for lasting for more than 7 days) and SARS-CoV-2 (OR 3.07, 95 % CI 1.89-5.01, p < 0.0001 for lasting for 3-7 days; OR 6.28, 95 % CI 3.53-11.18, p < 0.0001 for lasting for more than 7 days), compared with a transient lymphopenia of 1-2 days, while no significant association was found in other respiratory viruses. Prolonged lymphopenia was also associated with multi-organ damage in influenza and SARS-CoV-2 infections.Prolonged lymphopenia was significantly associated with worse clinical prognoses in influenza and SARS-CoV-2 infections, but not in other respiratory virus infections.