We previously corroborated benefits of the Trendelenburg position in the prevention of ventilator-associated pneumonia (VAP). We now investigate its potential effects on the brain versus the semirecumbent position. We studied 17 anesthetized pigs and randomized to be ventilated and positioned as follows: duty cycle (TI/TTOT) of 0.33, without positive end-expiratory pressure (PEEP), placed with the bed oriented 308 in anti-Trendelenburg (control group); positioned as in the control group, with TI/TTOT adjusted to achieve an expiratory flow bias, PEEP of 5cm H2O (IRV-PEEP); positioned in 58 TP and ventilated as in the control group (TP). Animalswere challenged into the oropharynx with Pseudomonas aeruginosa.We assessed hemodynamic parameters and systemic inflammation throughout the study. After 72 h, we evaluated incidence of microbiological/histological VAP and brain injury. Petechial hemorrhages score was greater in the TP group (P=0.013). Analysis of the dentate gyrus showed higher cell apoptosis and deteriorating neurons in TP animals (P<0.05 vs. the other groups). No differences in systemic inflammation were found among groups. Cerebral perfusion pressure was higher in TP animals (P<0.001), mainly driven by higher mean arterial pressure. Microbiological/histological VAP developed in 0%, 67%, and 86% of the animals in the TP, control, and IRV-PEEP groups, respectively (P=0.003). In conclusion, the TP prevents VAP; yet, we found deleterious neural effects in the dentate gyrus, likely associated with cerebrovascular modification in such position. Further laboratory and clinical studies are mandatory to appraise potential neurological risks associated with long-term TP.