Background: Mechanically ventilated patients usually present with larger amounts of pulmonary secretions because of impairment in mucociliary function and mucus transport. This can lead to pulmonary complications. Aims: To assess the acute response of MHI versus VHI in addition to chest physiotherapy on PaO2, PaCO2, PaO2/FiO2 ratio, and Compliance and sputum quantity in critically ill mechanically ventilated patients. Methods and Material: An experimental prospective comparative study was done. 30 participants between age groups of 20-60 years were included in the study and divided into two groups: Group A received MHI and chest physiotherapy & Group B received VHI and chest physiotherapy. Data was recorded in which sputum quantity was taken immediately after intervention and PaO2, PaCO2, PaO2/FiO2 ratio, Compliance were measured after 20 min of intervention and analyzed by paired t test and Kolmogorov Smirnov test. Results: The result showed that there was significant difference within the group but no significant difference (p=0.08) between the groups in the PaO2, PaCO2, PaO2/FiO2 ratio, and Compliance value after 20 min of intervention and there was no significant difference (p=0.08) in sputum quantity immediate after the intervention. Conclusion: The present study concludes that both manual hyperinflation and ventilator hyperinflation along with chest physiotherapy are equally better and effective in improving oxygenation, PaO2/FiO2 ratio, pulmonary compliance and lead to early extubation of patients. Further it states that there is no significant difference between MHI and VHI.