Background and objective Heparin-Induced Thrombocytopenia (HIT), if left untreated, can lead to thrombocytopenia, thromboembolic complications and even death. Two thrombin inhibitors, lepirudin and argatroban, have been shown to improve clinical outcomes compared to historical controls in the management of HIT. The purpose of this retrospective study was to compare the effects of lepirudin and argatroban in the management of HIT. Methods Adult subjects with a positive anti-heparin platelet factor 4 (PF4) antibody test and >50% decrease in platelet count during the first 30 days of admission over a period of 2 years were included in the study. Patient demographics, platelet counts, choice of antithrombin therapy, occurrence of thrombosis, length of hospital stay, and date and cause of death, if applicable, were collected for each patient. Results Eighty-two patients met inclusion criteria: 41 patients did not receive any thrombin inhibitors after the diagnosis of HIT, 24 patients received lepirudin and 17 patients received argatroban. Subjects treated with a thrombin inhibitor were more likely to experience platelet count recovery (87.5% for the lepirudin group and 82.4% for the argatroban group) compared to those who did not receive antithrombin therapy (51.2%) after the diagnosis of HIT was made (P < 0.001). The thrombosis rate for subjects who did not receive antithrombin therapy after the diagnosis of HIT was 26.8%, compared to 8.3% for the lepirudin group and 5.9% for the argatroban group (P < 0.01). The incidence of death was also higher in the group of subjects that did not receive antithrombin therapy (48.8%) compared with the lepirudin group (16.7%) or the argatroban group (23.5%), P < 0.01. Conclusion Our findings suggest that thrombin inhibitors can improve the outcomes of patients with HIT by decreasing the incidence of morbidity and mortality relating to HIT. No significant difference could be determined in outcomes between argatroban and lepirudin therapy.