The worldwide use of rail transport has increased, and the train speeds are escalating. Concurrently, the number of train disasters has been amplified globally. Consequently, railway safety has become an important issue for the future. High-velocity crashes increase the risk for injuries and mortality; nevertheless, there are relatively few studies on high-speed train crashes and the influencing factors on travelers' injuries occurring in the crash phase. The aim of this study was to investigate the fatal and non-fatal injuries and the main interacting factors that contributed to the injury process in the crash phase of the 2013 high-velocity train crash that occurred at Angrois, outside Santiago de Compostela, Spain. Hospital records (n=157) of all the injured who were admitted to the six hospitals in the region were reviewed and compiled by descriptive statistics. The instant fatalities (n=63) were collected on site. Influencing crash factors were observed on the crash site, by carriage inspections, and by reviewing official reports concerning the approximated train speed. The main interacting factors that contributed in the injury process in the crash phase were, among other things, the train speed, the design of the concrete structure of the curve, the robustness of the carriage exterior, and the interior environment of the carriages. Of the 222 people on board (218 passengers and four crew), 99% (n=220) were fatally or non-fatally injured in the crash. Thirty-three percent (n=72) suffered fatal injuries, of which 88% (n=63) died at the crash site and 13% (n=9) at the hospital. Twenty-one percent (n=32) of those admitted to hospital suffered multi-trauma (ie, extensive, severe, and/or critical injuries). The head, face, and neck sustained 42% (n=123) of the injuries followed by the trunk (chest, abdomen, and pelvis; n=92; 32%). Fractures were the most frequent (n=200; 69%) injury. A mass-casualty incident with an extensive amount of fatal, severe, and critical injuries is most probable with a high-velocity train; this presents prehospital challenges. This finding draws attention to the importance of more robust carriage exteriors and injury minimizing designs of both railway carriages and the surrounding environment to reduce injuries and fatalities in future high-speed crashes.