The mechanism underlying the spontaneous regression of neuroblastoma is unclear. Although it was hypothesized that this regression occurs via an immunological mechanism, there is no clinical evidence, and no animal models have been developed to investigate the involvement of immune systems, especially natural antibodies, against neuroblastoma. We performed an immunological analysis of homo- and heterozygous TH-MYCN transgenic mice as a model of aggressive neuroblastoma. Mice with no or small (<5 mm) tumors showed higher antibody titers in plasma than mice with large (>5 mm) tumors. A significant negative correlation was observed between the tumor diameter and the titer of antitumor antibody. This antibody had complement-dependent cytotoxicity but not antibody-dependent cellular cytotoxicity against neuroblastoma cells. Moreover, B-cell depletion had no effect on the tumor incidence in vivo. We revealed that TH-MYCN transgenic mice have a natural antibody against neuroblastoma that correlate with tumor size. However, this antibody does not correlate with the spontaneous regression of neuroblastoma. Thus, the function of the natural antibody is limited. (C) 2018 The Authors. Published by Elsevier Inc.