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Background: ABO blood groups are associated with different risk of viral infections. In vitro studies demonstrated how anti-A and anti-B antibodies neutralized the infectious capacity of SARS-CoV-2. Therefore, here we describe the inflammatory response of COVID-19 patients in the context of the blood group aiming to assess the lower severity status found in group O patients. Methods: Prospective and consecutive study including blood samples from 108 adult patients diagnosed with COVID-19 and admitted to the “Hospital Clinico Universitario” Valladolid, Spain between March 24 and April 11 2020. Patients were divided according to their ABO blood group. Plasma aliquots were analyzed, in duplicate, for the quantification of 45 mediators by MAGPIX system (Luminex). Statistical analysis was performed using the R statistical package version 4.0.2 Findings: We found a lower risk (2.16 times) of mechanical ventilation or death in patients with blood group O [Log Rank: p=0.042, Hazard Ratio: 0.463, CI 95% (0.213-1.004), p=0.050]. Moreover, 15 cytokines were significantly over-expressed (and only one under-expressed) in blood group O. Last, a multivariate model found BDNF, IL-13 and IL-27 as the best cytokines able to differentiate the immune profile based on blood group. Interpretation: Our cohort showed how blood group O was associated with both lower rates of hospital admission and a lower risk of intubation or death. Indeed, these patients produced higher amounts of cytokines in response to SARS-CoV-2, hence mounting an effective immune response which allowed them to control the viral infection and therefore decrease the risk of further complications. Funding Statement: This research was funded by Instituto de Salud Carlos III, grant number COV20/00491. Declaration of Interests: Alvaro Tamayo-Velasco declares no conflict of interest. - Maria Jesus Penarrubia-Ponce declares no conflict of interest. - Francisco Javier Alvarez declares no conflict of interest. - Hugo Gonzalo-Benito declares no conflict of interest. - Ignacio de la Fuente declares no conflict of interest. - Sonia Perez Gonzalez declares no conflict of interest. - Lucia Rico declares no conflict of interest. - Maria Teresa Jimenez-Garcia declares no conflict of interest. - Alba Sanchez-Rodriguez declares no conflict of interest. - Milagros Hijas-Villaizan declares no conflict of interest. - Marta Martin Fernandez declares no conflict of interest. - Carlos Duenas declares no conflict of interest. - Esther Gomez-Sanchez declares no conflict of interest. - Maria Heredia-Rodriguez declares no conflict of interest. - Oscar Gorgojo-Galindo declares no conflict of interest. - Itziar Fernandez declares no conflict of interest. - Lourdes del Rio declares no conflict of interest. - Irene Carnicero-Frutos declares no conflict of interest. - Maria Fe Munoz-Moreno declares no conflict of interest. - Eduardo Tamayo declares no conflict of interest. - David Bernardo declares no conflict of interest. - Pedro Martinez-Paz declares no conflict of interest. Ethics Approval Statement: The study was approved by the Hospital's Clinical Ethics Committee (CEIm) and approval was obtained from all study participants (cod: PI 20-1717).