Despite urgent need, no single strategy has been widely effective at controlling the growth of rapidly progressive solid tumors. We demonstrate here a potent antitumor therapy using modified bacterial DNA and toxin. Treatment of human head and neck cancer established as xenografts in athymic mice with immunostimulatory CpG oligodeoxynucleotides encapsulated in sterically stabilized cationic liposome [(CpG ODN)_SSCL] and recombinant interleukin-13 Pseudomonas exotoxin (IL13-PE) significantly reduced the tumor growth followed by complete regression in most animals. The antitumor activity of (CpG ODN)_SSCL was dependent on natural killer cells that infiltrated within tumors. Interestingly, IL13-PE enhanced (CpG ODN)_SSCL-induced natural killer cell activity and cytokine production in vivo and in vitro. These data strongly suggest that a combination of innate immune activation by (CpG ODN)_SSCL and tumor-directed targeting by IL13-PE is a novel approach for human cancer immunotherapy.