Subcutaneous methotrexate (sMTX) administration is considered more effective than the oral route due to better bioavailability and a lower rate of adverse drug reactions (ADRs); however, clinical data supporting this hypothesis is scarce.The aim of the study was to evaluate the efficacy and tolerability of sMTX in patients with active rheumatoid arthritis (RA), including a subset classified as an early stage of RA.A post-marketing, multicenter, open-label, non-randomized, non-interventional study enrolled 771 adult patients with active RA treated with sMTX (Metex®) for 2-6 weeks. The evaluation of therapy effectiveness (DAS28-ESR or DAS28-CRP) and monitoring of ADRs was an element of routine patient management. Therapy effectiveness was scored as the achievement of remission or response (according to European League Against Rheumatism (EULAR)).Among 761 (98.7%) patients that continued sMTX (after 25-31 weeks), clinical response was achieved by 69.5%, remission by 19.2% and low disease activity by 34.2%. Patients aged >60 years were less likely to achieve both remission (odds ratio (OR) = 0.61 (95% confidence interval (95% CI) = 0.39-0.93)) and clinical response (OR = 0.82 (95% CI = 0.71-0.95)), while overweight/obese patients (OR = 1.11 (95% CI = 1.00-1.24)) and those with early RA had greater chance to reach a clinical response (OR = 1.18 (95% CI = 1.03-1.34)). There were 16 ADRs (no serious or severe). In addition, at least 2-fold increase in alanine transaminase (ALT) activity was noted in 10 patients (1.3%).After 6-month therapy with sMTX, about 70% of patients with RA achieve a clinical response, and remission was observed in 20%. Younger age, overweight/obesity and an early stage of the disease are factors increasing therapy effectiveness; sMTX is well tolerated.