Critical COVID-19 is a life-threatening disease characterized by severe hypoxemia with complex pathophysiological mechanisms that are not yet completely understood. A pathological shift in the oxyhemoglobin curve (ODC) was previously described through the analysis of p50, intended as the oxygen tension at which hemoglobin is saturated by oxygen at 50%. The aim of this study was to analyze Hb-O₂affinity features over time in a cohort of critically ill COVID-19 patients, through the analysis of ODC p50 behavior. A retrospective analysis was performed; through multiple arterial blood gas (ABG) analyses, each p50 was calculated and normalized according to PaCO₂, pH and temperature; patients' p50 evolution over time was reported, comparing the first 3 days (early p50s) with the last 3 days (late p50s) of ICU stay. A total of 3514 ABG analyses of 32 consecutive patients were analyzed. The majority of patients presented a left shift over time (p= 0.03). A difference between early p50s and late p50s was found (20.63 ± 2.1 vs. 18.68 ± 3.3 mmHg,p= 0.03); median p50 of deceased patients showed more right shifts than those of alive patients (24.1 vs. 18.45 mmHg,p= 0.01). One-way ANOVA revealed a p50 variance greater in the early p50s (σ²= 8.6) than in the late p50s (σ²= 3.84), associated with a reduction over time (p< 0.001). Comparing the Hb-O₂affinity in critically ill COVID-19 patients between ICU admission and ICU discharge, a temporal shift in the ODC was observed.