Introduction: Ventilator-associated pneumonia (VAP) remains one of the most common nosocomial infections in the Intensive Care Unit. In the face of extremely high rates of antimicrobial resistance, it is essential to gauge the clinical significance of isolation of multidrug-resistant (MDR) pathogens from clinical samples. This study details the trend of VAP and the clinical significance of isolation of MDR pathogens from respiratory samples at an Indian tertiary care hospital. Methods: The study was conducted over a 5-year period. VAP was diagnosed on the basis of centres for disease control and prevention criteria. The trend in the rates was compared with preventive measures. Phenotypic and genotypic resistance to beta-lactamases was determined using standard methods. The correlation of isolation of a multi-resistant pathogen with the clinical outcome, length of stay and cost of antimicrobial was ascertained. A clone of Acinetobacter baumannii identified through multilocus sequence typing was used to answer the question of whether resistant bugs always have a fatal outcome. Results: The total ventilator days (VDs) for these patients amounted to 36,278. A total of 433 episodes of VAP occurred during the study, amounting to an overall VAP rate of 11.9/1000 VDs. There was a decline in the rates of VAP over the 5-year period, due to intensive surveillance and preventive activities. A. baumannii (54%) was the most common pathogen, followed by Pseudomonas aeruginosa (21%). A high rate of MDR was seen, with the presence of extended-spectrum beta-lactamases, AmpC and carbapenemase genes. The presence of MDR was not always associated with a fatal outcome. Conclusions: Isolation of MDR pathogens from bronchoalveolar lavage does not always adversely affect the outcome of patients. It requires an interdisciplinary team of clinical microbiologists, physicians and hospital infection control nurses, to collectively manage these patients.