Abstract Introduction Historically, management of frostbite followed the adage “freeze in January and amputate in July.” While rapid rewarming primarily addresses the ice crystal formation phase of damage, vascular injury and resulting thrombosis result in the overall tissue damage. Over the last two decades, limb salvage for frostbite has been widely employed. The use of tissue plasminogen activator (tPA) to prevent vascular thrombosis has been found to reduce the number of digit amputations and benefit of systemic thrombolytic therapy has been demonstrated. Post-thrombolysis anticoagulation has changed as well. Our institution has changed its protocol from using warfarin after tPA therapy to aspirin (ASA) for ease of adherence. This study evaluates the use of warfarin or aspirin for management after tPA therapy. Methods This was a retrospective review of patients who received tPA for frostbite between January 2008 and April 2019. Data collected included age, height, weight, sex, past medical history, contributing factors to development of frostbite, toxicology screen on admission, cold exposure time, rewarming time, number of digits/limbs affected, and highest grade of injury. Outcomes data included medications received, number of digits/limbs amputated, length of stay, and number of follow up visits. Results Ten patients were included in the statistical analysis, 7 patients in the ASA group and 3 patients in the warfarin group. Baseline demographics were similar between groups, except the ASA group was significantly younger (31.9 vs 64.7 years, p < 0.001) and weighed less (70.3 vs 86.8 kg, p = 0.02) than the warfarin group. Statistical analysis demonstrated no significant difference in outcomes when comparing patients managed with ASA 325 milligrams (mg) versus warfarin after tPA therapy. The average number of limbs amputated for patients taking ASA was 0 + 0.0 and was 0.7 + 1.2 for those taking warfarin (p=0.42). Average number of digits amputated for patients taking ASA and warfarin was 0.1 + 0.4 and 3.7 + 5.5, respectively (p=0.38). For patients who took ASA, length of hospital stay averaged at 8.0 + 4 days, while those who took warfarin stayed for 9.4 + 7.2 days (p= 0.64). Finally, the average number of follow up visits for patients who took ASA and warfarin was 3.9 + 4.7 and 8.0 + 9.6, respectively (p=0.37). Conclusions These findings indicate that there may not be a significant difference in clinical outcomes when comparing patients who took ASA to warfarin after tPA therapy. It is common for patients to have a delayed presentation and prolonged rewarming time, resulting in ineligibility to receive tPA. Single center frostbite studies are limited due to sample size and multi-centered studies are necessary for future studies. Applicability of Research to Practice ASA 325 mg daily may be a suitable alternative to warfarin therapy after tPA administration following a frostbite injury.