To investigate the contribution of a neutrophil response to the oncolytic effect of replicating attenuated measles virus (MV), MVs expressing murine granulocyte macrophage colony-stimulating factor (GM-CSF) were generated. The growth characteristics and kinetics of GM-CSF production of these viruses were characterized in vitro. Their biological effects were characterized in mice transgenic for the MV receptor CD46. The oncolytic efficacy of MV GM-CSF was then compared with that of a parental MV and a control, UV-irradiated MV using a human lymphoid tumor model in immunodeficient mice. Intratumoral injection of MV resulted in significant tumor regression or slowing of progression compared with injection of the control. Injection of MV GM-CSF further enhanced the oncolytic effect. In additional experiments, the cellular response to MV, MV GM-CSF, recombinant murine GM-CSF alone, or untreated tumors was quantified. The predominant response was an influx of neutrophils. Intratumoral natural killer cells and macrophages were not detected. The magnitude of the neutrophil response correlated well with tumor regression. Our studies suggest that therapy with replicating MV stimulates a strong neutrophil antitumor response, which can be cytokine-enhanced to improve oncolysis.