Two large phase-III prospective, multicenter, controlled, double-blind, randomized clinical trials (the PROTECT III study; the SYNAPSE study) evaluated the effectiveness of an early administration of progesterone in patients with moderate to severe traumatic brain injury (TBI). In the PROTECT III Trial, patients were included if the admission Glasgow Coma Scale (GCS) was within 4-12, whereas the SYNAPSE Trial only included patients with GCS 4-8. The total dose of progesterone was nearly similar in both studies and drug administration was initiated early after injury (within 4 hours for a total of 96 hours in PROTECT; within 8 hours for 120 hours in SYNAPSE). In the PROTECT Trial, primary outcome was 6-month favourable neurological outcome (defined using the Glasgow Outcome Scale), while in the SYNAPSE Trial it was the 6-month Glasgow Outcome Scale (GOS). Secondary outcomes, in both studies, included 6-month mortality. The PROTECT Trial was interrupted for futility after the second interim analysis (882 patients randomized out of the 1140 initially planned); the SYNAPSE Trial included 1195 patients. In PROTECT, the proportion of patients with favourable outcome was similar between groups (51% for progesterone vs. 56% for placebo; RR 3.03 [95% CI 1.96-4.66]); in SYNAPSE, no difference in GOS between the progesterone and placebo group was found (OR 0.96 [95% CI 0.77-1.18]). There was no difference in 6-month mortality or any of the other secondary outcomes between groups in the two trials. These studies demonstrated that early progesterone administration did not provide any benefit on the neurological recovery of TBI patients.