The effects of flow triggering (FT) as compared with pressure triggering (PT) on breathing effort have been the focus of several studies, and discrepant results have been reported. In the initial part of our study, a lung model was used to quantify triggering effort (airway pressure-time product, PTPaw) for a range of sensitivity settings in nine new-generation ventilators. A ventilator providing both FT and PT was then used to compare these systems during pressure-support (PSV) and volume-targeted assist-control ventilation (ACV) in eight ventilator-dependent patients, using sensitivity settings (2 L/min for FT and -2 cm H2O for PT) that had proven significantly different in the initial bench study. Indexes of effort included the esophageal and transdiaphragmatic pressure-time products and inspiratory work of breathing per minute (PTPes/min, PTPdi/min, and Wi/min, respectively). The experimental study revealed significant differences between ventilators in PTPaw at commonly used settings. In two of three ventilators featuring both systems, PTPaw was significantly lower with FT than PT (p < 0.001). In the clinical study, FT as compared with PT, was associated with reductions in all indexes of breathing effort during PSV: 16 +/- 6% (p < 0.001), 13 +/- 10% (p < 0.01), and 14 +/- 12% (p < 0.05) for PTPdi/min, PTPes/min, and Wi/min, respectively. By contrast, no differences were found when FT was used during ACV. Although FT reduced triggering effort in both modes (p < 0.001), the effects observed during the post-trigger phase differed, and explained the discrepant results between the two modes. We conclude that FT more effectively reduces breathing effort when used in conjunction with a pressure-targeted mode than with a volume-targeted mode, especially when flow delivery is close to or below demand.