The high mobility group box-1 (HMGB1) protein and NALP3 inflammasome have been identified to play important roles in inflammation and cancer pathogenesis, but the relationships between the two and cancer remain unclear. The current study investigated the relationship between HMGB1 and the NALP3 inflammasome in THP-1 macrophages. HMGB1 was found unable to activate the NALP3 inflammasome and failed to induce the release of the IL-1 beta and IL-18 in THP-1 macrophages. HMGB1 was also found significantly enhanced the activity of ATP to induce IL-1 beta and IL-18 by the induction of increased expression of pro-IL-1 beta and pro-IL-18. This process was dependent on activation of RAGE, MAPK p38 and NF-kappa B signaling pathway. These results demonstrate that HMGB1 promotes the synthesis of pro-IL-1 beta and pro-IL-18 in THP-1 macrophages by the activation of p38 MAPK and NF-kappa B through RAGE. HMGB1 likely plays an important role in the first step of the release of the IL-1 beta and IL-18, preparing for other cytokines to induce excessive release of IL-1 beta and IL-18 which promote inflammation and cancer progression.