High-risk behaviors leading to traffic fatalities are often a result of severe traumatic brain and spine injuries. The objective of the study was to analyze patterns of behavior in drivers and motorcyclists that are associated with central nervous system (CNS)-related prehospital deaths that may serve as a basis for future prevention initiatives. Our study group comprised 514 fatalities with severe CNS injuries documented at autopsy. The majority (n = 491) was the result of motor vehicle collisions (MVCs). In this group, male drivers predominated and the majority, 80 per cent, wore seatbelts. Toxicology analysis revealed 53 per cent of drivers with a mean concentration of ethanol above the legal limit. Texting while driving comprised 45 per cent of the study group. Less than 5 per cent of the fatalities were the result of road or weather conditions. In the motorcycle group (n = 23), 100 per cent of the victims were unhelmeted. We report a large autopsy series of CNS-related deaths with analysis of behavioral factors associated with the fatalities. Substance abuse and distracted driving are dominant patterns of high-risk behavior in MVCs and not wearing a motorcycle helmet is deadly for victims of motorcycle crashes.