Our understanding of the imunopathogenesis of juvenile idiopathic arthritis (JIA) is still incomplete. The aim of this study was to determine the significance of high mobility group box 1 (HMGB1), calcium-binding protein S100A12 and their soluble receptor for advanced glycation end products (sRAGE) in JIA. We included 102 children with JIA (28 childen with systemic-onset JIA, 39 children with oligoarticular-onset JIA, and 35 children with polyarticular-onset JIA) and 28 children as control group and harvested peripheral blood before any therapy was introduced. The serum levels of the alarmins were determined by ELISA, while gene expression in mononuclears was assessed by quantitative PCR. The level of the HMGB1 protein was significantly higher in the group of children with systemic JIA (sJIA), as compared to the olygoarticular (P < 0,000) or polyarticular (P < 0,002) subtype of JIA and control group (P < 0,032). The children with sJIA had a significant reduction of sRAGE protein in the serum (P < 0.036) and the gene expression (P < 0,007) of sRAGE. Additionally, serum HMGB1 in sJIA children was positively correlated with ESR (r = 0,51; P < 0,001), C-reactive protein (r=0,52; P < 0,000) levels and α2 globulin (r= 0,50; P < 0,001), while sRAGE serum level showed significantly close but inverse relationship with the same proteins of acute phase. These data indicate that HMGB1, a mediator of innate immunity, through interactions with sRAGE contributes to imunopathogenesis of sJIA. Furthermore, HMGB1 may serve as a biomarker for determining disease activity and a potential target of therapy in systemic JIA patients.