Frostbite can lead to severe consequences including loss of digits and limbs. One of the mechanisms of frostbite includes vascular thrombosis. The use of tissue plasminogen activator (tPA) in frostbite has been shown to be effective in case reports and small prospective studies. A retrospective chart review was performed on all patients admitted for frostbite between January 2008 and April 2015, and six patients were identified as having received treatment with intravenous tPA. Patients received an initial bolus dose followed by a 6-hour infusion of tPA. Five patients (83.3%) were treated with continuous infusion heparin following tPA administration. Three patients (50%) were discharged on aspirin 325 mg daily for 30 days and two patients (33.3%) were discharged on warfarin for 28 days. There were no serious complications noted with tPA. In this case series, there were 65 digits at risk for amputation in six patients. Only 16 digits (24.6%) were partially or completely amputated in three (50%) of the patients. After rapid rewarming, the use of tPA is safe and effective at reducing the number of digits amputated. Patients who had less of a response to tPA were those who had an unknown duration of cold exposure along with drug or alcohol intoxication at presentation. Utilizing a guideline with clear criteria will help facilitate determining appropriate patients to safely treat with tPA for frostbite injury.