To assess the serum interleukin (IL)-6 and IL-18 levels in patients with systemic juvenile idiopathic arthritis (s-JIA) and to identify the clinical features of patient subsets with different cytokine profiles, we analyzed the serum levels of IL-6 and IL-18 in patients with s-JIA and compared them with the clinical features of s-JIA. Eighteen patients were analyzed. IL-6 and IL-18 levels were quantified in serum by enzyme-linked immunosorbent assays. Interestingly, two distinct s-JIA patient subsets based on their serum IL-6 and IL-18 levels were identified: an IL-6 dominant and an IL-18 dominant. The serum IL-6 and IL-18 levels were consistent both at relapse and at the onset of s-JIA in each subset. The IL-6-dominant subset had a significantly greater number of joints with active disease and higher serum levels of matrix metalloproteinase-3, whereas the IL-18-dominant subset was more likely to develop macrophage activation syndrome (MAS). These findings indicate that two subsets of patients with s-JIA, one which is prone for arthritis and another with prone for MAS, can be identified on the basis of their serum IL-6 and IL-18 levels. These two subsets appear to be characterized by certain distinct clinical features.