To determine if selected cases of uterine serous carcinoma (USC) arise from tubal rather than endometrial epithelium. Bilateral fallopian tubes from 38 women with pure USC were entirely submitted for histopathologic examination using the protocol Sectioning and Extensively Examining the FIMbria (SEE-FIM). Non-neoplastic endometrium was extensively sampled. Immunohistochemistry for p53 was performed on all paraffin blocks of fallopian tube and non-neoplastic endometrium. Endometrial intraepithelial carcinoma (EIC) was present in 22 cases (58%). Endometrial p53 foci were identified in 3 patients. There were 11 cases (29%) with fallopian tube involvement; 9 of 11 had tubal wall invasion or lymphatic involvement without serous tubal intraepithelial carcinoma (STIC) and were, therefore, classified as metastatic from the endometrium. STIC was identified in 3 patients (8%). There were 3 cases with tubal p53 foci in non-neoplastic epithelium. EIC was present in 58% of patients, further supporting EIC as a precursor lesion to USC. STIC was present in 8%, suggesting that the fallopian tube may in fact represent the primary lesion in a minority of patients with USC. This finding may account for the early multifocal disease distribution observed in these patients.