BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that has spread rapidly worldwide. The role of immunosuppression among COVID-19 patients has not been elucidated and management may be challenging. OBJECTIVE: To assess differences in severe outcomes of hospitalized patients with COVID-19 according to immune system state. DESIGN: Retrospective single-center observational study with confirmed COVID-19 patients admitted to Hospital Universitario Ramón y Cajal from March 18, 2020 to April 04, 2020. The final date of follow-up was April 09, 2020.PARTICIPANTS: Confirmed COVID-19 patients. MAIN MEASURES: The primary endpoint was development of moderate-severe acute respiratory distress syndrome (ARDS). Time to moderate-severe ARDS, the need for mechanical or non-invasive ventilation (MV/NIV), death, and a composite of death or MV/NIV were secondary endpoints. KEY RESULTS: Of 138 patients included, 27 (19.6%) were immunosuppressed (IS), with 95 (68.8%) male patients and a median (Q1, Q3) age of 68 (54–78) years. Among the baseline characteristics, no relevant or significant differences were observed between IS and non-immunosuppressed (non-IS) patients, detecting a non-severe immunosupression among IS. A significantly lower proportion of IS patients (22.2% [95%CI, 9.8–43.0%]) compared to non-IS patients (49.5% [95%CI, 40.2–58.9%]) developed moderate-severe ARDS, in both unadjusted (OR 0.29 [95%CI, 0.11–0.76], p=0.014) and adjusted (aOR 0.16 [95%CI, 0.05–0.55], p=0.004) analyses. After stratifying by pathologies, only IS autoimmune diseases remained significant (aOR 0.12 [95%CI, 0.03–0.57], p=0.007). Non-significant trends toward a longer time to moderate or severe ARDS, a lower need for MV/NIV, and a lower risk of death or MV/NIV were detected in IS. CONCLUSIONS: In our cohort of COVID-19 patients, non-severe immunosuppression was associated with a lower risk of moderate-severe ARDS, especially among AD. This suggests a potential protective effect from a hypothesized host hyper-inflammatory response and warrants reconsideration of management of IS patients.