Background: Patients with RAS wild-type metastatic colorectal cancer (mCRC) in Spain may be treated with an epidermal growth factor receptor inhibitor: cetuximab (cet) or panitumumab (pan), in combination with chemotherapy (CT). Several factors may influence the choice of treatment regimen, including adverse event (AE) management, as cet- and pan-based therapies have distinct individual safety profiles. Patients may experience multiple adverse events during treatment. This study aimed to estimate the associated financial impact on Spain’s National Health System (SNHS). Methods: An economic model was developed to project the mean number of AEs per patient (p-p) and to estimate p-p and population-level costs of AE management (cAEm) associated with first-line cet+CT and pan+CT treatment regimens. Data on common and very common AEs and their severity were sourced from the summaries of product characteristics and a meta-analysis by Petrelli, et al. Categorical values were converted into numerical values using the mean values of the frequencies for each AE. Applicable resource costs were obtained from a Spanish database with health unit costs from official records, and from literature on oncology treatment-related costs. The eligible patient population was determined from published and grey literature, and market research. AEs of grade 1-2 were assumed to be treated in an outpatient setting, and those of grade 3-4 treated in an inpatient setting. The model inputs were validated by clinical oncologists in Spain. Results: An estimated 3,794 (cet+CT) and 2,325 (pan+CT) eligible patients received first-line treatment for mCRC. For patients receiving cet+CT or pan+CT, the average frequency of AEs p-p was estimated to be 7.2 (cet+CT) and 17.2 (pan+CT), with estimated p-p cAEms of €5,655 and €13,571, respectively. Conclusions: The lower rates of AEs for cet+CT may result in a reduced AE burden for eligible patients with mCRC, with estimated savings of €7,917 p-p on average. Although overall costs and clinical outcomes should be considered, treatment with cet+CT could yield annual cAEm savings for the SNHS of 35%. Future studies should consider the impact of AE management in a real-world setting.