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To explore the association between pulmonary artery systolic pressure (PASP) and success to wean from mechanical ventilation in COVID-19 patients.Thirty-four critically ill COVID-19 patients who had been placed on ventilator support were enrolled in this retrospective study and were divided into two groups: the weaning success group (group I) and the weaning failure group (group II). Physical examination, echocardiography, and routine laboratory test data were collected. The levels of troponin I, myoglobin, interleukin 6, and D-dimer were significantly lower in group I than in group II. The interventricular septum end-diastolic thickness (IVSd) was thicker (14.00 [13.50‒15.00] mm) and the PASP was higher (61.63 ± 13.53 mmHg) in group II. Logistic regression analysis showed that D-dimer and IVSd were factors associated with ventilator weaning. The odds ratio (OR) of D-dimer was 0.81 (95% CI 0.69‒0.95) and the OR of IVSd was 0.16 (95% CI 0.045‒0.59). Cox analysis revealed that the adjusted hazard ratio (HR) for a 1-mmHg increase in PASP was 0.94 (95% CI 0.90‒0.97) for weaning events (P < 0.001). PASP was negatively correlated with the PaO2:FiO2 (r = -0.48, P < 0.01). A receiver operating characteristic curve showed that the best cutoff value of PASP for ventilator weaning was 39.50 mmHg, with a sensitivity of 100% and a specificity of 96.15% PASP was an independent risk factor for the difficulty of weaning severely ill COVID-19 patients off mechanical ventilation. PASP can be used as one of the indicators for evaluating the condition of COVID-19 patients.