Animal studies routinely demonstrate an alcohol (ETOH) -mediated increase in survival after experimental traumatic brain injury (TBI). Recent clinical studies also suggest ETOH plays a neuroprotective role in moderate to severe TBI. We sought to investigate the relationship between ETOH and outcomes in patients with moderate to severe TBI using a countywide database. The Los Angeles County Trauma System database was queried for all adult (older than 14 years) patients with isolated moderate to severe TBI trauma (head Abbreviated Injury Score [AIS] 3 or greater, all other AIS 3 or less) who had ETOH levels measured on admission between 1998 and 2005. A total of 7304 patients were evaluated with 3219 (44.1%) patients testing positive for serum ETOH. ETOH-positive patients with TBI had a significantly lower mortality rate compared with ETOH negative patients (8.5 vs. 10.5%, P = 0.005). Even after logistic regression analysis, a positive ETOH was associated with reduced mortality (adjusted OR 0.82, 95% CI: 0.69-0.99, P = 0.035). Therefore, a positive serum ETOH level was independently associated with significantly improved survival in patients with isolated moderate to severe TBI. The neuroprotective role ETOH plays in TBI is in contrast to previous findings and deserves further attention as a potential therapeutic.