OBJECTIVE: The association between anti-TNF therapy and increased rate of infection is widely documented in adults with rheumatoid arthritis. Findings in children with juvenile idiopathic arthritis (JIA) have been less well documented. The aims of this analysis were (1) to compare rates of medically significant infection (MSI) in children with JIA treated with etanercept (ETN) versus methotrexate (MTX) and (2) to compare rates between ETN-MTX in combination and ETN monotherapy. METHODS: To 31/5/2013, 852 ETN and 260 MTX treated children had been recruited to the BSPAR Etanercept Cohort Study. MSIs included infections resulting in death, hospitalisation, or deemed medically significant by clinicians. This on-drug analysis followed patients until first MSI, death, treatment discontinuation or last follow-up. Cox proportional hazards models adjusted using propensity deciles (PD) compared rates of MSI between cohorts. Sensitivity analyses were conducted looking specifically at serious infections (SI) defined as requiring hospitalisation or IV antibiotics/anti-virals. RESULTS: The ETN-treated cohort was older with longer disease duration but disease activity was similar between the cohorts. 133 first MSIs were reported (109 on ETN, 24 MTX). Patients receiving ETN had higher rates of MSI than controls (PD adjusted hazard ratio 2.13 (1.22, 3.74)). The risk of MSI was higher whether patients were receiving combination or monotherapy. Sensitivity analysis showed no difference in SI rate between treatment groups, which were much less common. CONCLUSION: ETN therapy is associated with an increased risk of MSI, however this disappears when looking at SIs, suggesting either differences in infection severity and/or possible reporting bias. This article is protected by copyright. All rights reserved.