BACKGROUND With regard to the improved surgical possibilities and the rising tendency of attempted limb salvage, the topic of secondary amputation becomes increasingly important. The aim of this study was to identify potential prognostic factors predicting secondary amputation in third-degree open lower limb fractures. METHODS All patients experienced third-degree open fractures of the lower limb without primary amputation (1994–2012). Prognostic factors were investigated to explain the final outcome of these patients (limb salvage vs. secondary amputation). RESULTS From a total of 408 open diaphyseal tibia fractures, 93 consecutive fractures were identified (Gustilo-Anderson [G/A] type IIIA, n = 38; G/A type IIIB, n = 41; G/A type IIIC, n = 14) including seven patients with primary amputation. Definite limb salvage was achieved in 72 patients (88%), whereas in 10 patients (12%), secondary amputation was necessary. The median time to secondary amputation was 12 days (range, 2–1,573 days). The median Injury Severity Score (ISS) was 11 (range, 9–41), and the median Mangled Extremity Severity Score (MESS) was 4 (range, 2–9). The MESS was significantly higher in the amputation group compared with the limb salvage group (p = 0.0001). Furthermore, statistical testing revealed that the amount of complex fractures (p = 0.0132), the soft tissue damage (p = 0.0050), the vascular injury rate (p = 0.0110) and the fasciotomy rate (p = 0.0468) were significantly higher in the amputation group. In 60%, the limitations for limb salvage were infectious complications and/or, in 40%, was irreversible vessel occlusion after initial vessel reconstruction. CONCLUSION The current study findings indicate that MESS is highly prognostic, but considering the significant advances in reconstructive techniques, decision making in patients with an MESS of 7 or greater should be reevaluated for the everyday clinical use. LEVEL OF EVIDENCE Prognostic study, level III. Therapeutic study, level IV.