Background: Despite remarkable progress that has been achieved in the recent years in the diagnosis, prevention, and therapy for ventilator-associated pneumonia (VAP), this disease continues to create complication during the course of treatment in a significant proportion of patients while receiving mechanical ventilation. Objective: This study was designed to evaluate the effect of multimodality chest physiotherapy in intubated and mechanically ventilated patients undergoing treatment in the intensive care units (ICUs) for prevention of VAP. Patients and Methods: A total of 101 adult intubated and mechanically ventilated patients were included in this study. Manual hyperinflation (MH) and suctioning were administered to patients in the control group (n = 51), and positioning and chest wall vibrations in addition to MH plus suctioning (multimodality chest physiotherapy) were administered to patients in the study group (n = 50) till they were extubated. Both the groups were subjected to treatment twice a day. Standard care in the form of routine nursing care, pharmacological therapy, inhalation therapy, as advised by the concerned physician/surgeon was strictly implemented throughout the intervention period. Results: Data were analyzed using SPSS window version 9.0. The Clinical Pulmonary infection Score (CPIS) Score showed significant decrease at the end of extubation/successful outcome or discharge in both the groups (P = 0.00). In addition, significant decrease in mortality rate was noted in the study group (24%) as compared to the control group (49%) (P = 0.007). Conclusions: It was observed in this study that twice-daily multimodality chest physiotherapy was associated with a significant decrease in the CPIS Scores in the study group as compared to the control group suggesting a decrease in the occurrence of VAP. There was also a significant reduction in the mortality rates with the use of multimodality chest physiotherapy in mechanically ventilated patients.