Abstract Introduction One of the most challenging complications in musculoskeletal trauma surgery is the development of infection after fracture fixation (IAFF). It can delay healing, lead to permanent functional loss, or even amputation of the affected limb. The main goal of this study was to investigate the total healthcare costs and length-of-stay (LOS) related to the surgical treatment of tibia fractures and furthermore identify the subset of clinical variables driving these costs within the Belgian healthcare system. The hypothesis was that deep infection would be the most important driver for total healthcare costs. Patients and methods Overall, 358 patients treated operatively for AO/OTA type 41, 42, and 43 tibia fractures between January 1, 2009 and January 1, 2014 were included in this study. A total of 26 clinical and process variables were defined. Calculated costs were limited to hospital care covered by the Belgian healthcare financing system. The five main cost categories studied were: honoraria, materials, hospitalization, day care admission, and pharmaceuticals. Results Multivariate analysis showed that deep infection was the most significant characteristic driving total healthcare costs and LOS related to the surgical treatment of tibia fractures. Furthermore, this complication resulted in the highest overall increase in total healthcare costs and LOS. Treatment costs were approximately 6.5-times higher compared to uninfected patients. Conclusion This study shows the enormous hospital-related healthcare costs associated with IAFF of the tibia. Treatment costs for patients with deep infection are higher than previously mentioned in the literature. Therefore, future research should focus more on prevention rather than treatment strategies, not only to reduce patient morbidity but also to reduce the socio-economic impact.