The relationship between ligand-receptor affinity and antitumor potency of an oncolytic virus was investigated using a panel of six HER2/neu (HER2)-targeted measles viruses (MVs) displaying single-chain antibodies (scFv) that bind to the same epitope on HER2, but with affinities ranging from 10(-6) to 10(-11) M. All viruses were able to infect SKOV3ip.1 human ovarian cancer cells in vitro, but only the high-affinity MV (Kd≥10(-8) M) induced cytopathic effects of syncytia formation in the cell monolayers. In contrast, all six viruses were therapeutically active in vivo against orthotopic human ovarian SKOV3ip.1 tumor xenografts in athymic mice compared with saline-treated controls. The oncolytic activities of MV displaying the high-affinity scFv (Kd=10(-9), 10(-10), 10(-11) M) were not significantly superior to MV displaying scFv with Kd of 10(-8) M or less. Results from this study suggest that increasing the receptor affinity of the attachment protein of an oncolytic MV has minimal impact on its in vivo efficacy against a tumor that expresses the targeted receptor.