Direct tumor injections of CpG (ODN #1826) into murine tumors markedly suppressed the tumor growth and increased the survival of the mice. Tumor growth was reduced by 60-67% in Colon Tumor 26 (CT-26) and B-16 melanoma tumors treated with CpG as compared to untreated one. In CT-26 and B-16 tumors treated with CpG, the average survival of the animals were prolonged to 26 and 28 d as compared to 16 and 18 d in control respectively. Long-term surviving animals in CT-26 tumor groups were also protected from a subsequent injection of a lethal dose of tumor cells. In the present study, effect of CpG was mediated through CD8(+) T cells, as their depletion resulted in the abrogation of the therapeutic effects of the CpG. It suggests that direct tumor injection might be a simple means of achieving a clinical response in cancer patients.