Background. Newcastle disease virus (NDV) is a paramyxovirus that is pathogenic in birds but causes only mild flulike symptoms in human beings. NDV(F3aa)-GFP is a genetically modified, fusogenic NDV. We assessed the utility of NDV(F3aa)-GFP in treating head and neck squamous cell carcinoma. Methods and Results. At a multiplicity of infection (MOI) of 1, NDV(F3aa)-GFP infection of 3 cell lines supported strong GFP expression by 36 hours. Four cell lines were highly sensitivite to viral cytotoxicity, with > 75% of cells lysed by day 6 at MOI 0.1, and 2 other cell lines were partially susceptible. Murine SCC25 flank tumors exhibited robust GFP expression after a single intratumoral viral injection and showed near-complete tumor regression over 34 days. There were no adverse effects attributable to therapy. Conclusions. We demonstrate that a fusogenic NDV exerts potent oncolytic effects against human head and neck cancer and support its continued investigation for clinical application. (C) 2010 Wiley Periodicals, Inc. Head Neck 33: 1394-1399, 2011