Background: Ventilator-associated pneumonia (VAP) is the most widespread and life-threatening nosocomial infection in intensive care units (ICUs). The duration of antibiotic use is a good predictor of prognosis in patients with VAP, but the ideal duration of antibiotic therapy for VAP in critically ill patients has not been confirmed. Research is therefore needed into the optimal duration of antibiotic use and its impact on VAP. Methods: The Medical Information Mart for Intensive Care database included 1,609 patients with VAP. Chi-square or Student's t-tests were used to compare groups, and Cox regression analysis was used to investigate the factors influencing the prognoses of patients with VAP. Nonlinear tests were performed on antibiotic use lasting <7, 7-10, and >10 days. Significant factors were included in the model for sensitivity analysis. For the subgroup analyses, the body mass indexes (BMIs) of patients were separated into BMI <30 kg/m2 and BMI ≥30 kg/m2, with the criterion of statistical significance set at p < 0.05. Restricted cubic splines were used to analyze the relationship between antibiotic use duration and mortality risk in patients with VAP. Results: In patients with VAP, the effects of antibiotic use duration on the outcomes were nonlinear. Antibiotic use for 7-10 days in models 1-3 increased the risk of antibiotic use by 2.6020-, 2.1642-, and 2.3263-fold relative to for >10 days, respectively. The risks in models 1-3 for <7 days were 2.6510-, 1.9933-, and 2.5151-fold higher than those in models with >10 days of antibiotic use, respectively. These results were robust across the analyses. Conclusions: The duration of antibiotic treatment had a nonlinear effect on the prognosis of patients with VAP. Antibiotic use durations of <7 days and 7-10 days both presented risks, and the appropriate duration of antibiotic use can ensure the good prognosis of patients with VAP.Copyright © 2022 Xu, Han, Xu, Shen, Zheng, Wang and Lyu.