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Objective: To elucidate the impact of lymphopenia on critical COVID-19 patient outcomes., Methods: We conducted a multicenter prospective cohort study across five hospitals in Portugal and Brazil from 2020 to 2021. The study included adult patients admitted to the intensive care unit with SARS-CoV-2 pneumonia. Patients were categorized into two groups based on their lymphocyte counts within 48 hours of intensive care unit admission: the Lymphopenia Group (lymphocyte serum count < 1 × 109/L) and the Nonlymphopenia Group. Multivariate logistic regression, propensity score matching, Kaplan‒Meier survival curve analysis and Cox proportional hazards regression analysis were used., Results: A total of 912 patients were enrolled, with 191 (20.9%) in the Nonlymphopenia Group and 721 (79.1%) in the Lymphopenia Group. Lymphopenia patients displayed significantly elevated disease severity indices, including Sequential Organ Failure Assessment and Simplified Acute Physiology Score 3 scores, at intensive care unit admission (p = 0.001 and p < 0.001, respectively). Additionally, they presented heightened requirements for vasopressor support (p = 0.045) and prolonged intensive care unit and in-hospital stays (both p < 0.001). Multivariate logistic regression analysis after propensity score matching revealed a significant contribution of lymphopenia to mortality, with an odds ratio of 1,621 (95%CI: 1,275 - 2,048; p < 0.001). Interaction models revealed an increase of 8% in mortality for each decade of longevity in patients with concomitant lymphopenia. In the subanalysis utilizing three-group stratification, the Severe Lymphopenia Group had the highest mortality rate, not only in direct comparisons but also in Kaplan‒Meier survival analysis (log-rank test p = 0.0048)., Conclusion: Lymphopenia in COVID-19 patients is associated with increased disease severity and an increased risk of mortality, underscoring the need for prompt support for critically ill high-risk patients. These findings offer important insights into improving patient care strategies for COVID-19 patients.