The effect of positive end-expiratory pressure (PEEP) on intracranial pressure (ICP) had never been studied in obese patients with severe brain injury (SBI). The main aim was to evaluate the effect of PEEP on ICP in SBI patients with mechanical ventilation according to obesity status.SBI patients admitted to the ICU with mechanical ventilation between 2014 and 2015 were included. Demographic, hemodynamic, arterial blood gas, and ventilator data at the time of the paired PEEP and ICP observations were recorded and compared between obese (body mass index ≥ 30 kg/m2) and non-obese SBI patients. Generalized estimating equation (GEE) model was used to assess the relationship between PEEP and ICP in obese and non-obese SBI patients, respectively.Six hundred twenty-seven SBI patients were included, 407 (65%) non-obese and 220 (35%) obese patients. A total of 30,415 paired PEEP and ICP observations were recorded in these patients, 19,566 (64.3%) for non-obese and 10,849 (35.7%) for obese. In the multivariable analysis, a statistically significant relationship between PEEP and ICP was found in obese SBI patients, but not in non-obese ones. For every cmH2O increase in PEEP, there was a 0.19 mmHg increase in ICP (95% CI [0.05, 0.33], P = 0.007) and a 0.15 mmHg decrease in CPP (95% CI [-0.29, -0.01], P = 0.036) in obese SBI patients after adjusting for confounders.The results suggested that, contrary to non-obese SBI patients, the application of PEEP may produce an increase in ICP in obese SBI patients. However, the effect was modest and may be clinically inconsequential.© 2022. The Author(s).