BACKGROUND: An increasing number of studies have investigated the clinical epidemiology and outcomes of ventilator-associated pneumonia (VAP) in intensive care units. However, these findings have not been clearly defined in broad subgroups of mechanically ventilated adults. Hence, this protocol for a systematic review and meta-analysis is designed to better understand the clinical and epidemiological features of VAP in these patient populations by establishing its overall prognosis of and risk factors for morbidity and mortality and to determine the differences in clinical and economic outcomes between VAP and non-VAP patients. METHODS: This present review will systematically search available full-text articles without date and language restrictions and indexed in PubMed, CENTRAL, CINAHL, Web of Science, and EMBASE databases. In addition, reference lists and citations of retrieved articles and relevant medical and nursing journals will be manually reviewed. Supplementary search in other databases involving trials, reviews, and grey literatures, including conference proceedings, theses, and dissertations, will be performed. Study investigators will be contacted to clarify missing or unpublished data. All prognostic studies meeting the pre-defined eligibility criteria will be included. The study selection, risk of bias assessment, data extraction, and grading of the quality of evidence will be carried out in duplicate, involving independent evaluation by two investigators with consensus or a third-party adjudication. The degree of inter-rater agreement will be calculated using the kappa statistic. For meta-analysis, dichotomous and continuous outcome measures will be pooled using odds ratios and standardized mean differences with 95% confidence intervals, respectively. The Mantel-Haenszel or inverse variance methods with random effects model will be used as a guide for analysis. The heterogeneity of each outcome measure will be assessed using both X2 and I2 statistics. In addition, sensitivity and subgroup analyses will be performed to ensure consistency of pooled results. The review protocol described herein is in accordance with the PRISMA-P standards. DISCUSSION: The investigation of the epidemiological profiles, prognostic factors, and outcomes associated with VAP is critical for the identification of high-risk groups of mechanically ventilated patients and evaluation of possible clinical endpoints. This may provide substantial links for improved VAP prevention practices targeting modifiable risk factors. Implications for future research directions are discussed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017048158.