Neuroblastoma (NB) is the most common extra-cranial solid tumor in children. Since intensive therapeutic intervention does not prolong the overall disease-free survival rate for this tumor, novel therapeutic strategies are required. NB tumor, but not normal tissues, over-express the disialoganglioside (GD(2)) at the cell surface. In this study we developed a novel immunoliposomal formulation by covalently coupled Fab' fragments of the monoclonal antibody anti-GD(2) to Stealth liposomes (Fab'-SIL). In vitro experiments showed specific, competitive binding to, and uptake by various NB cell lines. Moreover, doxorubicin-loaded immunoliposomes (Fab'-SIL[DXR]) presented increased selectivity and efficacy in inhibiting NB cell proliferation compared to free drug and non-targeted liposomes (SL[DXR]). The in vivo cytotoxic effectiveness of different liposomal formulations encapsulating DXR was tested against an experimental metastatic model of human NB in nude mice. Long term survivors were obtained in mice treated with Fab'-SIL[DXR], but not in untreated animals or those treated with free anti-GD(2) Fab' fragments, Fab'-SIL (no drug), free-DXR or SL[DXR] (P<0.0001). Fab'-SIL[DXR] prevented the establishment and the metastatic growth of the tumor cells in all organs examined. In conclusion, Fab'-SIL[DXR] formulations should receive clinical evaluation as adjuvant therapy of neuroblastoma.