Background: The heterogeneity of acute respiratory distress syndrome (ARDS) patients is a challenge for the development of effective treatments. This study aimed to identify and characterize novel respiratory subphenotypes of COVID-19 ARDS, with potential implications for targeted patient management. Methods: Consecutive ventilated patients with PCR-confirmed COVID-19 infection, in which prone positioning was clinically indicated for moderate or severe ARDS, were included in a prospective cohort. The patients were assigned to development or validation cohorts based on a temporal split. The PaO2/FiO2 ratio, respiratory compliance, and ventilatory ratio were assessed longitudinally throughout the first prone session. The subphenotypes were derived and validated using machine learning techniques. A K-means clustering implementation designed for joint trajectory analysis was utilized for the unsupervised classification of the development cohort. A random forest model was trained on the labeled development cohort and used to validate the subphenotypes in the validation cohort. Results: 718 patients were included in a prospective cohort analysis. Of those, 504 were assigned to the development cohort and 214 to the validation cohort. Two distinct subphenotypes, labeled A and B, were identified. Subphenotype B had a lower PaO2/FiO2 response during the prone session, higher ventilatory ratio, and lower compliance than subphenotype A. Subphenotype B had a higher proportion of females (p < 0.001) and lung disease (p = 0.005), higher baseline SAPS III (p = 0.002) and SOFA (p < 0.001) scores, and lower body mass index (p = 0.05). Subphenotype B had also higher levels of the pro-inflammatory biomarker IL-6 (p = 0.017). Subphenotype B was independently associated with an increased risk of 60-day mortality (OR 1.89, 95% CI 1.51-2.36). Additionally, Subphenotype B was associated with a lower number of ventilator-free days on day 28 (p < 0.001) and a lower hospital length of stay (p < 0.001). The subphenotypes were reproducible in the validation cohort. Conclusion: Our study successfully identified and validated two distinct subphenotypes of COVID-19 ARDS based on key respiratory parameters. The findings suggest potential implications for better patient stratification, risk assessment, and treatment personalization. Future research is warranted to explore the utility of these novel subphenotypes for guiding targeted therapeutic strategies in COVID-19 ARDS.