Complement activation has been reported after major trauma. However, little is known about the clinical relevance and the mechanisms of complement activation early after trauma. Therefore, the aim of this study was to measure complement activation, to identify the roles of injury severity and hypoperfusion, to determine the predominant activated pathway, and to identify the clinical significance of early complement activation in trauma patients. A total of 208 adult trauma patients were enrolled in this prospective single-center cohort study of major trauma patients. Blood samples were obtained within 30 min after injury before any significant fluid resuscitation. Complement (C5b-9) was activated early after trauma, correlated with injury severity and tissue hypoperfusion, and was associated with increased mortality rate and with the development of organ failure such as acute lung injury and acute renal failure. The alternative pathway seems to be the predominant activated complement pathway early after trauma. However, the classical and/or the lectin pathway initiated complement activation because of the correlation between plasma levels of C4d and C3a/C5b-9. Finally, in patients with low C3a levels, C5b-9 levels correlated with plasma levels of prothrombin fragments 1 + 2, a marker of thrombin generation, suggesting additional C3-independent complement activation by thrombin after severe trauma. In summary, complement activation via its amplification by the alternative pathway is observed early after trauma and correlates with injury severity, tissue hypoperfusion, and worse clinical outcomes. Besides complement activation by the classical and/or lectin pathways, there is an independent association between thrombin generation and complement activation.