Rationale: Subglottic secretion drainage (SSD) appears to be effective in preventing VAP, primarily by reducing early-onset pneumonia; but it may not prevent late-onset pneumonia. We tested the hypothesis using an endotracheal tube incorporating an ultrathin polyurethane cuff (which reduces channel formation and fluid leakage from the subglottic area), in addition to a SSD lumen, which would reduce the incidence of lateonset VAP. Objective: To compare the incidence of ventilator-associated pneumonia (VAP) using an endotracheal tube with polyurethane cuff and subglottic secretion drainage (ETTPUC-SSD) versus a conventional endotracheal tube (ETT-C) with polyvinyl cuff, without subglottic secretion drainage Methods: Clinical randomized trial in a 24-bed medical-surgical intensive care unit. Patients expected to require mechanical ventilation for more than 24 hours were randomly assigned to one of two groups: one was ventilated with ETT-PUC-SSD and the other with ETT-C. Measurements: Tracheal aspirate samples were obtained during endotracheal intubation, then twice a week and finally on extubation. Main Results: VAP was found in 31 of 140 (22.1%) patients in the ETT-C group and 11 of 140 (7.9%) in the ETT-PUC-SSD group (p=0.001). Cox regression analysis showed ETT-C as risk factor for global VAP (Hazard Ratio=3.3; 95% confidence interval = 1.66-6.67; p=0.001), early-onset VAP (Hazard Ratio=3.3; 95% confidence interval = 1.19-9.09; p=0.02) and late-onset VAP (Hazard Ratio=3.5; 95% confidence interval = 1.34-9.01; p=0.01). Conclusion: The use of an endotracheal tube with polyurethane cuff and subglottic secretion drainage helps prevent early and late-onset VAP.