In this retrospective case-control study conducted in Cluj-Napoca, Romania, we assessed the effect of ulcerations/amputations on hospitalization costs of patients with diabetes. Patients with (Group 1) or without (Group 2) ulcerations/amputations (case-control ratio 3:1) admitted to a single diabetes center between 2012-2017 were included. The effects of hospitalization days, age, duration of diabetes, body mass index and glycated hemoglobin (HbA1c) on total costs was explored using a multivariate linear regression analysis, enter model. Overall, 876 patients were included (Group 1: 682, 323 [47.4%] with amputations; Group 2: 194). Median (interquartile range) total expenses in Group 1 were 40% higher compared to Group 2 (€724 [504; 1186] vs €517 [362; 645], p < 0.001). Significant differences were observed between hospitalization costs (p < 0.001), cost of food (p < 0.001), medication (p = 0.044), drugs administered at the emergency room/intensive care unit (p < 0.001) and other expenses (p = 0.003). Hospitalization costs represented 80.5% of total expenses in Group 1 and 76.3% in Group 2. In multivariate analysis, hospitalization days influenced significantly the total costs in both groups (p < 0.001); in Group 2, the effect of HbA1c was also significant (p = 0.021). Diabetic foot ulcers and subsequent amputations most likely impose a significant economic burden on the Romanian public healthcare system.