Mortality is higher in patients with traumatic brain injury (TBI) resuscitated with albumin compared to saline, but the mechanism for increased mortality is unknown. In patients from the Saline vs. Albumin Fluid Evaluation (SAFE) study with TBI who underwent ICP monitoring, interventional data were collected from randomization to day 14 to determine changes in ICP (primary outcome) and in therapies used to treat increased ICP. Pattern mixture modelling, designed to address informative dropouts, was used to compare temporal changes between the albumin and saline groups. 321 patients were identified, of whom 164 (51.1 ) received albumin and 157 (48.9 ) saline. There was a significant linear increase in mean ICP and significantly more deaths in the albumin group compared to saline when ICP monitoring was ceased during the first week (1.30?0.33 vs. -0.37?0.36, p=0.0006; and 34.4 vs. 17.4 ; p=0.006 respectively), but not when monitoring ceased during the second week (-0.08?0.44 vs. -0.23?0.38, p=0.79; and 18.6 vs. 12.1 ; p=0.36 respectively). There were statistically significant differences in the mean total daily doses of morphine (-0.42?0.07 vs. -0.66?0.0, p=0.0009), propofol (-0.45?0.11 vs. -0.76?0.11; p=0.034) and norepinephrine (-0.50?0.07 vs. -0.74?0.07) and in temperature (0.03 ? 0.03 vs. 0.16 ? 0.03; p=0.0014) between the albumin and saline groups when ICP monitoring ceased during the first week. The use of albumin for resuscitation in patients with severe TBI is associated with increased ICP during the first week. This is the most likely mechanism of increased mortality in these patients.