Introduction The objective of this work is to measure the economic and epidemiological impact of the implementation of a comprehensive quality improvement plan (CQIP) for the prevention and reduction of ventilator-associated pneumonia (VAP) in the adult intensive care unit in a Mexican hospital. Materials and Methods A cross-sectional, ambispective, comparative, analytical, observational study was conducted with epidemiological data on cases of health care–associated infections and with information from the Hospital Epidemiological Surveillance Unit from August 2017 to July 2018. Results Before to the implementation of the CQIP, there were a total of 26 VAPs, with a rate of 32.2 per 1000 ventilator-days. After the implementation of CQIP, there were 14 VAPs, with a rate of 23.4 per 1000 ventilator-days, with a 46.2% decrease in incidence ( P = 0.02). Before the installation of the interventions, the expense was $4,471,073.80, with an average cost per case of $171,964.38. The total cost per bed-day in the adult intensive care unit was $331,280.00, and for hospitalization, the cost was $192,038.00; for the use of antimicrobials, an expense of $749,689.20 was calculated, and for the use of mechanical ventilation, the cost was $2,974,275.60. The percentage of decrease in the cost of VAP after CQIP implementation was 46.5%. Conclusions The implementation of CQIP based on the risk evaluation factors of VAP resulted in their decrease, which is reflected in a patient safety and quality care improvement.