Objectives: The aim of this study was to review side effects on MTX reported to HALMED and compare them with side effects in the EudraVigilance database and to find a comparison of their occurrence with the occurrences in the SmPC. Also, this paper discusses some of the security issues with MTX. Materials and methods: Adverse reactions were analyzed by gender and patient age, categorization of adverse effects according to the MedDRA organ system classification. The total number of suspected adverse reactions to the MTX side effects of the Croatian Agency for Medicinal Products and Medicinal Products through the years 1993 to 2018 was analyzed. Results: The first reported suspected adverse reaction of MTX in Croatia was in 1993, and by 2018, a total of 217 suspected adverse reaction reports were recorded. Overall, 72 percent of MTX side effects were reported by HALMED in women, and EudraVigilance had the highest reported rate in women by 63 percent. The most common side effects reported to HALMED's database were ones affecting the digestive system with 50.4 percent, while in EudraVigilance, the most adverse reactions were categorized as "general disorders and reactions at the site of application". The largest number of applications in HALMEDs database include those in people between 18 and 64 years of age, 59.8 percent. The highest proportion of adverse reactions observed in EudraVigilance was in the same age group, but also in EudraVigilance, 15.1 percent more adverse reactions were observed in persons 65 years and older. Adverse reactions listed in the SmPC are appropriate by the frequency and affiliation to organ systems recorded in the EudraVigilance Adverse Reaction Database. By 2019, 7 safety issues related to MTX have been addressed by PRAC, one of which resulted in an addition to the SmPC regarding the appearance of pulmonary alveolar hemorrhage. Conclusions: From year to year, there is an increasing number of spontaneous reports of suspected side effects of MTX to both HALMED and the EudraVigilance database. The side effects noted in EudraVigilance correspond to the respective proportions and types mentioned in the SmPC. Due to a wide dosage range for different indications there is an increase in the likelihood of misdosing. Safety measures have been put in place to prevent such events and the education of patients and medical professionals should reduce the number of such events.