The first reported case of vaginal serous papillary adenocarcinoma (VSPA) in a 61-year-old woman is presented. The woman had a mass in the upper posterior vaginal wall that was 2.5 cm in maximal dimension and was treated with a radical hysterectomy with bilateral salpingo-oophorectomy, lymphadenectomy, and subtotal vaginectomy, followed by radiation therapy. The ovaries, fallopian tubes, cervix, endometrium, and peritoneum did not show primary or secondary neoplastic involvement. The patient died because of recurrent disease in the form of widespread peritoneal metastases 30 months postoperatively. Microscopically, the tumor was similar to serous papillary adenocarcinoma of the ovary (OSPA). Immunohistochemical studies showed positive staining for CA 125, CA19.9, DUPAN-2, and TAG-72, and negative staining for CEA. Cytogenetic analysis showed chromosome 6 abnormalities similar to those found in OSPA. These results suggest that VSPA is a clinically aggressive primary tumor sharing morphological and cytogenetic analogy with OSPA.