OBJECTIVES: To assess and compare the costs of first-line monoclonal antibodies (mABs) treatment protocols in breast cancer, non-Hodgkin lymphoma and colorectal carcinoma in South-Εastern Europe. METHODS: A retrospective, bottom-up case series study design was implemented with one-year time horizon and payer’s perspective. The study sample size was 265 patients (breast cancer, N=137, colorectal cancer, N=44, and non-Hodgkin lymphoma, N=84) while treatment protocols included adjuvant mAbs: trastuzumab (N=137), bevacizumab (N=28), cetuximab (N=16) and rituximab (N=84). ICD-10 related,direct medical and lost productivity costs (€) across treatment groups during 2010-2013. RESULTS: The average length of observation was 128±97 days per patient. Total mean direct and indirect costs of care were: trastuzumab breast cancer group €17,740; bevacizumab colorectal carcinoma group €8,775; cetuximab colorectal carcinoma group €27,181 and rituximab non-Hodgkin lymphoma group €19,431An average mAbs-treated patient incurred €17,897 costs of medical care. The total combined budget of these 265 patients was €4,742,775. CONCLUSIONS: The use of mAbs strongly correlated with high costs in first-line cancer medical care and dominated other cost domains. Cetuximab-based treatment protocol in colorectal carcinoma patients was substantially more expensive compared to trastuzumab (C50); bevacizumab (C20) and rituximab (C80) alternatives. Extremely high costs of mAbs are the key-issue for Eastern European policy makers by crossing the upper limits of affordability in middle-income economies.