Oligodeoxynucleotides containing CpG motifs (CpG-ODN) are powerful immunostimulating agents that are currently entering clinical trials in various human diseases. Concerns exist about potential auto-immune diseases triggered by such treatment. We thus investigated whether tumor rejection induced by CpG-ODN treatment could lead to a harmful auto-immune reaction against the nervous system (neurological paraneoplastic disease) at the time of acute tumor rejection, or in long-term surviving animals. Mice bearing established neuroblastomas were treated with intra-tumoral injections of CpG-ODN, resulting in tumor inhibition and tumor rejection in one-third of the animals. Immunocytochemistry and Western blot studies revealed no specific anti-neuronal antibodies. None of the animals developed neurological disabilities and histological studies of the nervous system were normal. CpG-ODN can therefore trigger neuroblastoma rejection without inducing neurological paraneoplastic disease.