Little is known about the safety and efficacy of etanercept in children below the age of 4 years. Twenty-five patients with juvenile idiopathic arthritis (JIA) below the age of 4 years, who received etanercept, were documented in the German JIA Etanercept Registry. Patients with the nonsystemic JIA disease-subtype responded more frequently to treatment with etanercept than systemic onset patients. At last observation, two (20%) of the nonsystemic patients did not reach a PedACR 30 response, while six (40%) of the systemic onset patients did not respond to the therapy. Complete resolution of symptoms was observed in two (20%) nonsystemic and in five (33%) systemic onset patients with JIA. Tolerability was good with only two infections occurring in the total patients group. Patients with JIA below the age of 4 years, with a methotrexate-resistant disease course, would also benefit from treatment with etanercept, showing a good tolerability. The restriction to children older than 4 years appears to be artificial without any good rationale.