Background: Mechanical ventilation of intensive care patients results in inspiratory muscle weakness. Inspiratory muscle training may be useful, but no studies have specifically described the physiological response to training. Research questions: Is inspiratory muscle training with a threshold device safe in selected ventilator-dependent patients? Does inspiratory muscle strength increase with high-intensity inspiratory muscle training in ventilator-dependent patients? Design: Prospective cohort study of 10 medically stable ventilator-dependent adult patients. Setting: Tertiary adult intensive care unit. Methods: Inspiratory muscle training 5-6 days per week with a threshold device attached to the tracheostomy without supplemental oxygen. Outcome measures: Physiological response to training (heart rate, mean arterial pressure, oxygen saturation and respiratory rate), adverse events, training pressures. Results: No adverse events were recorded in 195 sessions studied. For each patient's second training session, no significant changes in heart rate (Mean Difference 1.3bpm, 95% CI -2.7 to 5.3), mean arterial pressure (Mean Difference -0.9mmHg, 95% CI -6.4 to 4.6), respiratory rate (Mean Difference 1.2bpm, 95% CI -1.1 to 3.5bpm) or oxygen saturation (Mean Difference 1.2%, 95% CI -0.6 to 3.0) were detected Training pressures increased significantly (Mean Difference 18.6cmH 2O, 95% CI 11.8-25.3). Conclusion: Threshold-based inspiratory muscle training can be delivered safely in selected ventilator-dependent patients without supplemental oxygen. Inspiratory muscle training is associated with increased muscle strength, which may assist ventilatory weaning.