High-grade serous ovarian carcinoma presents significant clinical and therapeutic challenges. Although the traditional model of carcinogenesis has focused on the ovary as a tumor initiation site, recent studies suggest that there may be additional sites of origin outside the ovary, namely the secretory cells of the fallopian tube. Our study demonstrates that high-grade serous tumors can originate in fallopian tubal secretory epithelial cells and also establishes serous tubal intraepithelial carcinoma as the precursor lesion to high-grade serous ovarian and peritoneal carcinomas in animal models targeting the Brca, Tp53, and Pten genes. These findings offer an avenue to address clinically important questions that are critical for cancer prevention and early detection in women carrying BRCA1 and BRCA2 mutations. •PAX8 can drive murine high-grade serous tumors originating in the fallopian tube•Early alterations in Brca, Tp53, and Pten lead to intraepithelial precursor lesions•Genomic analysis of Pax8-driven tumors shows strong correlation with human tumors•High-grade serous ovarian cancer can arise from the fallopian tubal secretory cell