The aim of the current study was to investigate the differential effects of endotracheal suction on respiratory mechanics and gas exchange in patients with severe sepsis using pressure-controlled ventilation (PCV) and volume-controlled ventilation (VCV). We prospectively included 76 patients with severe sepsis receiving mechanical ventilation due to acute respiratory failure (ARF). The effects of endotracheal suction on respiratory mechanics and gas exchange during VCV and PCV were compared. PCV used an inspiratory pressure that caused the same tidal volume (VT) as that of VCV; a VT of 9 mL/kg predicted body weight and an 8.0 mm inner-diameter endotracheal tube were used. Patients underwent suction for 15 s using an open suction system with 12F catheters connected to a 150 mmHg vacuum. VT was decreased by 28.9% and 27.8% at 1 min and 10 min after suction compared with the baseline when using PCV, and compliance decreased by 31.4% and 30.3% (P<0.05), respectively. When using VCV, the airway peak pressure (Ppeak) was increased by 31.5% and 28.0% at 1 and 10 min, respectively, after suction compared with the baseline; airway plateau pressure (Pplat) increased by 22.0% and 22.9%, and compliance decreased by 34.4% and 33.2% (P<0.05). In PCV, PaO2 was increased by 6.8% and 12.4% at 3 min and 10 min, respectively, after suctioning, compared to respective increases of 18.9% and 29.6% observed using VCV (P<0.05). In PCV, the difference in PaO2 at 10 min after suctioning compared with the baseline was significant (72.5 ± 16.9 vs. 87.5 ± 17.2 mmHg; P<0.05). In VCV, no significant difference was observed (84.5 ± 17.1 vs. 86.1 ± 14.7 mmHg; P>0.05). Endotracheal suction may impair gas exchange and respiratory mechanics in patients with severe sepsis under both PCV and VCV, but the effects on gas exchange recover quickly under VCV.