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Clostridium difficile TcdB is a key virulence factor that causes C. difficile-associated diseases. Our previous studies have shown that recombinant full-length TcdB (rTcdB) induces cell death in CT26 cells, and rTcdB-treated CT26 cells with high immunogenicity could stimulate dendritic cell (DC) activation and T cell activation in vitro. The rTcdB-treated CT26 cells also induce antitumor immunity in mice and protect mice from CT26 cells. High-mobility group box 1 protein (HMGB1) is a non-histone nuclear protein, which has various biological functions within the nucleus and also acts as an extracellular signal molecule involving in inflammatory diseases, cancers or autoimmune diseases. In this study, HMGB1 was found to be released from the rTcdB-treated CT26 cells. HMGB1 knockdown by using specific siRNA weakened the capacity of the BMDCs loaded with the rTcdB-treated CT26 cells to prime T cells in vitro and in vivo. The released HMGB1 from CT26 cells could interact with the receptor TLR4, which is closely related to DC activation and immune responses. The knockdown of HMGB1 also affected the phagocytosis of the rTcdB-treated CT26 cells by DCs in vitro. Furthermore, HMGB1 weakened the antitumor immunity of the rTcdB-treated CT26 cells, which protects mice from rechallenge of the live CT26 cells. Taken together, these results suggest that HMGB1 plays an important role on the immunogenicity of the rTcdB-treated dying CT26 cells.