The HSV-1 1716 mutant virus and similar oncolytic herpesviruses deficient in the gamma 34.5 neurovirulence gene are able to reduce the growth of tumors in mice. Here we demonstrate that HSV-1 1716 therapy moderately reduced the growth of tumors of the highly malignant, spontaneously metastasizing 4T1 mouse mammary carcinoma model. This moderate effect on 4T1 tumor growth was likely due to poor replication kinetics of HSV-1 1716 in 4T1 cells. Interestingly, HSV-1 therapy of the primary tumor increased the survival time of mice. Coincident with this increase was a reduction in metastases as determined by quantification of the number of metastatic cells in the lungs. HSV-1 therapy of the primary tumor was also able to reduce the establishment of a second challenge of 4T1 tumors. Moreover, infiltrates of both CD4(+) and CD8(+) T cells were detected in HSV-1 1716-treated tumors. An important role for the T cell infiltrates was confirmed when HSV-1 therapy did not reduce the growth of 4T1 tumors in SCID mice. Collectively, these results demonstrate that an HSV-dependent anti-tumor immune response is required for the reduction in primary 4T1 tumor growth and for the reduction in the establishment of metastases in this tumor model.