The aim of this study was to evaluate whether pressure support ventilation (PSV) requires different diaphragmatic efforts and patient-ventilator matching, according to the underlying disease. Four groups of patients requiring PSV were studied: Group A, recovering from an episode of acute respiratory failure due to adult respiratory distress syndrome (ARDS); Group B, with postsurgical complications; and two subsets of chronic obstructive pulmonary disease (COPD) patients, with "normal" static compliance of the respiratory system (Cst,rs) (Group C) or elevated Cst,rs (Group D). Ventilatory pattern, transdiaphragmatic pressure (Pdi), the pressure-time product of the diaphragm (PTPdi), static (PEEPi,stat) and dynamic intrinsic positive end-expiratory pressure (PEEPi,dyn), Cst,rs and resistance of the total respiratory system (Rrs) were recorded. The matching between patient and ventilator was analysed, recording the number of "ineffective efforts" (inspiratory efforts not efficient enough to trigger a new ventilator cycle, despite a positive deflection in Pdi). A satisfactory blood gas equilibrium arterial oxygen saturation (Sa,O2 > 93%, with a pH > 7.32) was obtained in the various groups with different levels of PSV. Minute ventilation was found to be significantly higher in Groups A and B, due to the longer expiratory time (tE) in the COPD groups. Group A (2 out of 7), Group B (3 out of 7), Group C (3 out of 5) patients showed sporadic "ineffective efforts". All Group D patients manifested continuous mismatching with the ventilator, so that the pressure-time product of the diaphragm per minute (PTPdi/min), reflecting the metabolic work of the diaphragm, was not different in the four groups. Tidal volume and the spontaneous inspiratory efforts were similar in the four groups, but the number of breaths delivered by the ventilator was significantly higher in Groups A and B. The application of different levels of pressure support ventilation in patients with acute respiratory failure due to different pathologies, led them to breathe with comparable pressure time product of the diaphragm. The majority of the patients showed mismatching with the ventilator, although this effect was more pronounced in the groups with chronic obstructive pulmonary disease.