This Clinical Practice Guideline addresses severe frostbite treatment. We defined severe frostbite as atmospheric cooling that results in a perfusion deficit to the extremities. We limited our review to adults and excluded cold contact or rapid freeze injuries that resulted in isolated devitalized tissue. After developing population, intervention, comparator, outcomes (PICO) questions, a comprehensive literature search was conducted with the help of a professional medical librarian. Available literature was reviewed and systematically evaluated. Recommendations based on the available scientific evidence were formulated through consensus of a multidisciplinary committee. We conditionally recommend the use of rapid rewarming in a 38 to 42°C water bath and the use of thrombolytics for fewer amputations and/or a more distal level of amputation. We conditionally recommend the use of "early" administration of thrombolytics ( ≤ 12 hours from rewarming) compared to "later" administration of thrombolytics for fewer amputations and/or a more distal level of amputation. No recommendation could be formed on the use of vascular imaging studies to determine the use of and/or the time to initiate thrombolytic therapy. No recommendation could be formed on the use of intravenous thrombolytics compared to the use of intra-arterial thrombolytics on fewer amputations and/or a more distal level of amputation. No recommendation could be formed on the use of iloprost resulting in fewer amputations and/or more distal levels of amputation. No recommendation could be formed on the use of diagnostic imaging modalities for surgical planning on fewer amputations, a more distal level of amputation, or earlier timing of amputation.