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Composition of the intestinal microbiome has been shown to impact generation of a tumor-specific immune response following chemotherapy and immune checkpoint blockade. We hypothesized that the local and intestinal microbiota may also impact immune activation and radiation response. We prospectively assessed the microbiota and T-cell repertoire of 30 cervical cancer patients throughout CRT. Greater diversity of the intestinal microbiome was associated with exceptional response and development of clonal T-cell expansion. Predominance of immunosuppressive Lactobacillus species in the cervix was associated with failure to expand clonal T-cells and decreased relapse-free survival. Patients with a robust response to CRT developed clonal expansion of T-cells, suggesting that highly radiation responsive cervical cancers generate an antigen specific immune response. Depletion of gut microbiome diversity and presence of vaginal Lactobacillus were associated with decreased presence of activated CD8 T-cell infiltration and decreased radiation response in an orthotopic model of HPV cancer, suggesting that microbial diversity is required for generation of effective antitumor immunity in radiation responsive HPV cancers.