Renal cell carcinoma easily develops metastasis, which is highly resistant to a variety of therapies. Oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODN) are potent activators of innate and adaptive immunity. CpG ODN is inclined to be used as vaccine adjuvant or in combination with other therapies to exert antitumor effect mediated by the adaptive immunity. Herein, we examined the antitumor effect of CpG ODN monotherapy and the role of innate immunity on human RCC Caki-1 cells xenografted in nude mice. Our results indicated that the peritumoral subcutaneous injections of CpG ODN1826 once a week resulted in significant inhibition of the growth of Caki-1 xenografts compared with the control groups, and the survival of tumor-bearing mice were also prolonged significantly. When cytotoxicity of splenic cells from host mice was assessed, it was found that CpG ODN1826 significantly promoted the cytotoxicities of splenocytes targeting primary Caki-1 cells or YAC-1 cells, indicating that the activity of natural killer cells in tumor-bearing nude mice was enhanced by CpG ODN1826 monotherapy. The serum concentrations of interleukin-12 were increased in mice treated with CpG ODN1826. Thus, CpG ODN1826 monotherapy induces significant inhibitory effects on the growth of human RCC xenografted in athymic immunodeficient mice, and the tumor-bearing mice achieves long-term survival, which might be attributed to enhanced innate immunity.