AbstractCOVID‐19 significantly impairs survival rates among hematological patients when compared to the general population. Our prospective multicentre project analyzed early administration of anti‐SARS‐CoV‐2 spike protein neutralizing monoclonal antibodies (NmAbs) – bamlanivimab (72%) and casirivimab/imdevimab (28%) – efficacy among hematological patients with early‐stage COVID‐19. Mortality rate was compared to a control cohort of 575 SARS‐CoV‐2 positive hematological patients untreated with any specific anti‐COVID‐19 therapy. 88 hematological patients with lymphomas, acute leukemias, and myeloma as their most frequent underlying diagnoses (72%) were evaluated with a 97 days median follow‐up after NmAb administration. One third of patients (32%) were treated with an anti‐CD20 monoclonal antibody before COVID‐19 diagnosis. Median time between first COVID‐19 symptom and NmAb administration was 2 days. When administering NmAb, 29%, 57%, 11%, 2%, and 1% of our patients had asymptomatic, mild, moderate, severe, and critical degrees of COVID‐19, respectively. 80% of baseline asymptomatic patients remained asymptomatic following NmAb administration. Median duration of COVID‐19 symptoms after NmAb administration was 2.5 days. Progression to severe/critical COVID‐19 occurred among a total of 17% (15/88) of our cases and numerically higher with bamlanivimab versus casirivimab/imdevimab (21% vs. 8%; p = 0.215), and myelomas (29%), lymphomas (17%) and acute leukemias (18%), respectively. During final follow‐up, nine deaths (10%) were recorded ‐ all after bamlanivimab (p = 0.056) with 8% attributed to COVID‐19. Regarding “remdesivir/convalescent plasma naïve” patients, COVID‐19 mortality rates were significantly lower in our NmAbs treated cohort compared to the control cohort of untreated SARS‐CoV‐2 positive hematological patients (6% vs. 16%, p = 0.020), respectively. Our study validated the safety and efficacy of NmAbs early use among hematological patients with newly diagnosed early‐stage COVID‐19 in terms of alleviating infection course and decreasing mortality. Results confirmed a more positive effect of a casirivimab/imdevimab combination versus bamlanivimab monotherapy.