Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex 1 virus (HSV-1), approved for cancer therapy. We investigated its effect on the clinical, histological, single-cell transcriptomic and immune repertoire level using repeated fine-needle aspirates (FNAs) of injected and noninjected lesions in primary cutaneous B-cell lymphoma (pCBCL). Thirteen patients received intralesional T-VEC, eleven of which demonstrated tumor response in the injected lesions. Upon single cell sequencing of the FNAs, we identified the malignant population and separated three pCBCL subtypes. HSV-1T-VEC transcripts were detected 24h after injection in malignant and non-malignant cells of the injected lesion but were absent in the noninjected lesion. Oncolytic virotherapy resulted in a rapid eradication of malignant cells by more than one death mechanism, IFN pathway activation, early influx of NK cells, monocytes, dendritic cells, followed by an enrichment in clonal cytotoxic T-cells and decrease of regulatory T-cells in both injected and noninjected lesions.