Abstract Immune tolerance is a major mechanism involved in the development of hepatocellular carcinoma (HCC). We have previously showed, in a mouse model of spontaneous HCC, that T cell response can be induced in mice with small HCC, but not in mice with large HCC, indicating that immune tolerance occurs when tumors grow to a certain size. The mechanisms responsible for this phenomenon were not clear. In this study, we compared freshly isolated liver dendritic cell (DC) subsets in mice with no tumor, small HCC, and large HCC. We found that total numbers of CD11c+ hepatic DC were comparable in these 3 groups. However, CD11cint B220+ subset of 'plasmacytoid' DC (pDC) significantly decreased in both small and large HCC-bearing mice. Importantly, CD11chi B220- subset of mature DC significantly increased in mice with small HCC. In contrast, CD11chi B220- subset of mature DC remains same in mice with large HCC, the CD11cint B220- subset of immature DC increased instead in these mice. The surface phenotype of each subset of DCs were examined and demonstrated higher level of CD86 and CD40 expression by CD11chi subset of mature DC comparing with CD11cint subsets. These findings indicate that modulating subset distribution of liver DC, such as inhibiting the expansion of CD11chi B220- subset of mature DC, may play a role in immune tolerance to HCC.