Infectious mononucleosis (IM) is a viral disease caused by Epstein-Barr virus (EBV) or cytomegalovirus (CMV) affecting all age groups. While EBV causes IM in majority of population, CMV can cause severe forms of IM in immunocompromised patients. High prevalence and incidence of IM and substantial vibrance of the symptoms, IM requires consideration of various treatment methods, with a particular focus on the cost-effectiveness of hospitalization compared to day hospital treatment. Objective: The study focused on analyzing the cost-effectiveness of treating patients with IM by comparing treatment costs in the Inpatient Department and the Day Hospital of the Clinic for Infectious Diseases at the Clinical Hospital Center Rijeka. The aim was to identify the more efficient treatment modality to highlight the proper allocation of resources. Methods: A retrospective approach was used to collect data, allowing for a detailed analysis of IM patients at the Clinic for Infectious Diseases at KBC Rijeka. The study population consisted of 100 patients, equally distributed between the two treatment modalities (Inpatient Department / Day Hospital). Data were collected on the sociodemographic characteristics of the participants, clinical parameters of the disease, treatment costs, and treatment outcomes. Results: The analysis of treatment costs in the Inpatient Department and Day Hospital demonstrated the effectiveness of both treatment modalities for IM. It was found that the Day Hospital enables effective treatment while reducing costs and hospital capacity, whereas hospitalization is justified in cases of severe disease complications. Conclusion: The study identified the importance of cost-effectiveness analysis in the management of healthcare system resources. Tailoring healthcare to the individual needs of patients, identifying the most effective therapeutic strategies, and reducing the costs of prolonged hospitalization are key findings of the research. These results provide a foundation for improving healthcare practices and optimizing the healthcare system in the context of infectious mononucleosis.