Systemic-onset juvenile idiopathic arthritis (JIA) is a severe and steroid-dependent disease, which sometimes progresses to the fatal disease macrophage activation syndrome. An investigation of inflammatory cytokine levels revealed increases in IL-6 in serum of systemic-onset disease patients. Continuously elevated levels of IL-6 in serum may play a important role in manifesting the clinical symptoms and signs of systemic-onset JIA, including spiking fever, rash, arthritis, and serositis. The characteristic fever spikes parallel IL-6 levels. Long-term exposure to high levels of IL-6 in children results in severe growth impairment, which was strongly suggested by the recent establishment of IL-6 transgenic mice. To avoid disease progression to macrophage activation syndrome and the adverse effects of high-dose corticosteroids, it might be reasonable to inhibit the formation of IL-6/IL-6R complex in order to block the binding to gp130 receptor, a biologically active receptor for IL-6. This review will provide evidence of the relationship between IL-6 homeostasis and systemic-onset JIA, and our recent trials of anti-IL-6R antibody (MRA) for children with acute systemic disease intractable to long-term and high-dose corticosteroid therapy. MRA could be a therapeutic modality for children with systemic-onset JIA intractable to high-dose corticosteroids.