Objective: To investigate the effects of manual chest compression (MCC) on the expiratory flow bias during the positive end-expiratory pressure-zero end-expiratory pressure (PEEP-ZEEP) airway clearance maneuver applied in patients on mechanical ventilation. The flow bias, which influences pulmonary secretion removal, is evaluated by the ratio and difference between the peak expiratory flow (PEF) and the peak inspiratory flow (PIF). Methods: This was a crossover randomized study involving 10 patients. The PEEP-ZEEP maneuver was applied at four time points, one without MCC and the other three with MCC, which were performed by three different respiratory therapists. Respiratory mechanics data were obtained with a specific monitor. Results: The PEEP-ZEEP maneuver without MCC was enough to exceed the threshold that is considered necessary to move secretion toward the glottis (PEF − PIF difference > 33 L/min): a mean PEF − PIF difference of 49.1 ± 9.4 L/min was achieved. The mean PEF/PIF ratio achieved was 3.3 ± 0.7. Using MCC with PEEP-ZEEP increased the mean PEF − PIF difference by 6.7 ± 3.4 L/min. We found a moderate correlation between respiratory therapist hand grip strength and the flow bias generated with MCC. No adverse hemodynamic or respiratory effects were found. Conclusions: The PEEP-ZEEP maneuver, without MCC, resulted in an expiratory flow bias superior to that necessary to facilitate pulmonary secretion removal. Combining MCC with the PEEP-ZEEP maneuver increased the expiratory flow bias, which increases the potential of the maneuver to remove secretions.