Vaginal cancer is a rare yet aggressive cancer, with unmet need for novel therapeutics. In this case report, we present a patient with advanced stage, HPV-positive vaginal cancer who demonstrated clinical, radiologic, and molecular response to combination treatment of antibody drug conjugate Enfortumab Vedotin (EV) with Pembrolizumab. The patient had positive Nectin-4 staining on evaluation, raising the possibility for future clinical application of EV in vaginal squamous cell cancer.