Background: Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer. Most patients exhibit clinically detectable metastases at diagnosis and have an extremely poor prognosis despite combined modality therapy. HuD-antigen is a neuronal RNA-binding protein that is expressed in 100% of SCLC tumor cells. High levels of circulating anti-HuD antibodies in patients appear to be linked to spontaneous remission of their SCLC. This suggests that the HuD-antigen might be a potential molecular target for SCLC immunotargeting therapy. Methods: We constructed a new antibody-toxin compound (BW-2) comprised of mouse-anti-human-HuD mAb bound to saporin and tested the compound in vitro in the NCI-H69 SCLC cell line. In vivo SCLC experiments utilized male athymic nude mice (NCRNUM) xenografted with NCI-H69 cells. Tumor xenografted mice received a single intravenous or intratumoral injection of BW-2, while control tumor xenografted mice were treated with either anti-HuD antibody or saporin alone. Normal C57BL/6 mice were used to test for potential neurological side effects from BW-2. Results: In vitro experiments showed a high level of HuD+ tumor cell specific cytotoxicity in the presence of BW-2 immunotoxin and minimal HuD- cell cytotoxicity only at much higher concentrations of BW-2. Immunotoxin therapy in a nude mouse model of human SCLC demonstrated clear tumor shrinking while control tumor xenografted mice demonstrated rapid tumor volume expansion. Tumor volume in immunotoxin treated mice regressed for several weeks. Neurological testing revealed no manifestations of neurological disease in normal C57BL/6 mice even at doses of BW-2 as high as 10mg/kg. Conclusions: Our findings demonstrate in vitro and in vivo effectiveness of anti-HuD immunotoxin therapy for HuD+ SCLC. This approach to tumor antigen specific immunotargeting therapy may one day provide an additional treatment for SCLC.