Background Methotrexate (MTX) is a first-line therapy for rheumatoid arthritis (RA) and widely used in psoriatic arthritis (PsA). Therapy is often interrupted due to adverse events, comorbidities and patient or disease-related factors. This study evaluated patterns, reasons, and outcomes of MTX discontinuation and resumption in routine practice.MethodsThis single-center, retrospective study reviewed medical records of 100 adults (50 RA, 50 PsA) who received oral MTX between 2015 and 2023. MTX discontinuation was defined as therapy cessation or a gap >60 days and resumption as any reinitiation post-discontinuation. Successful resumption required continuation for ≥3 months with documented disease stability or improvement, with or without dose adjustment. Associations were analyzed using χ², t-tests, Mann–Whitney U, and trend analyses, with p<0.05 considered significant.ResultsRA patients had a higher comorbidity burden and longer MTX exposure than PsA patients. ADRs were the leading cause of discontinuation in RA (n=28, 56%), whereas inefficacy (n=10, 20%) and patient preference (n=16, 32%) predominated in PsA. MTX resumption was attempted in 26 RA (52%) and 28 PsA (56%) patients, with success in 16 RA (32%) and 18 PsA (36%). Dose adjustments were required in 16 RA (32%) and 22 PsA (44%), and ADR recurrence occurred in 6 patients (12%) in both groups. Higher comorbidity burden was significantly associated with increased ADRs and lower likelihood of successful resumption. Conclusion MTX discontinuation and resumption patterns differ between RA and PsA and are influenced by comorbidity burden. Individualized management and monitoring may improve MTX persistence and outcomes.