Receptors for conserved molecular patterns associated with microbial pathogens induce synthesis of co‐stimulatory molecules and cytokines in immature dendritic cells (DC), as do antigen‐reactive CD4 T helper cells via CD40 signaling. Once activated, antigen‐presenting DC may activate CD8 T cell responses in a T helper cell‐independent fashion. Using immunostimulatory CpG‐oligonucleotides (ODN) mimicking bacterial CpG‐DNA, we tested whether CpG‐DNA bypasses the need for T helper cells in CTL responses towards proteins by directly activating antigen‐presenting DC to transit into professional APC. We describe that immature DC in situ constitutively process soluble proteins and generate CD8 T cell determinants yet CD8 T cell responses remain abortive. Induction of primary antigen‐specific CD8 cytotoxic T lymphocyte (CTL)‐mediated responses becomes initiated in wild‐type as well as T helper cell‐deficient mice, provided soluble protein and CpG‐ODN are draining into the same lymph node. Specifically we show that CpG‐ODN trigger antigen‐presenting immature DC within the draining lymph node to acutely up‐regulate co‐stimulatory molecules and produce IL‐12. These results provide new insights for generating in vivo efficient CTL responses to soluble proteins which may influence vaccination strategies.