Dendritic cell (DC) vaccine is a promising immunotherapy for malignancies, but its clinical efficacy has been questioned. Here we examined the mechanisms of treatment failure with DC vaccine in a murine colon cancer model. DC vaccination of naive mice prevents tumor implantation, but it is ineffective in tumor-bearing hosts despite the induction of tumor-specific CTL activity. Analyses of tumor-specific T helper cell type 1 (Th1)/T helper cell type 2 (Th2) responses showed that DC vaccine induced a mixed Th1/Th2 response in naive mice. Interestingly, CD4+ T cells from tumor-bearing mice showed a Th1-predominant response before DC vaccination but Th2 after DC vaccination. Furthermore, interleukin-10 production was higher in CD4+ T cells from vaccinated tumor-bearing mice than in CD4+ T cells from unvaccinated tumor-bearing mice. CD4+ T cells from mice treated with lipopolysaccharide (LPS)-matured DC fusion vaccine had lower production of interleukin-10 than CD4+ T cells from mice treated with non-LPS-treated DC vaccine. However, similar to the non-LPS-treated DC vaccine, the LPS-matured DC vaccine failed to suppress tumor growth and induced a Th2 predominant tumor-specific response in tumor-bearing mice. These results suggest that the presence of tumor in the host induces an aberrant CD4+ T cell response to DC vaccine, which may contribute to the failure of the vaccine to eradicate established tumors.