Background: Uterine serous carcinoma is a less common subtype of endometrial cancer that is associated with poorer survival. The optimal post-operative adjuvant treatment strategy for these patients remains uncertain. Methods: This multi-institutional, retrospective cohort study evaluated patients with early stage uterine serous carcinoma. Patients with FIGO Stage IA-II disease after surgery, whose tumors had serous or mixed serous/non-serous histology were included. Patients with carcinosarcoma were excluded. Clinical data were abstracted from local medical records. Summary statistics, Fisher’s exact, and Kruskal-Wallis tests were used to analyze demographic and clinical characteristics. Univariable and multivariable analyses were performed for recurrence-free survival (RFS) and overall survival (OS). Results: 634 patients were included. 77% of patients had Stage IA disease, 42% showed no myometrial invasion. The majority had pure serous histology (72%) and LVSI (76%). Adjuvant treatment varied: 12% received no adjuvant therapy, 7% had chemotherapy alone, 51% had cuff brachytherapy, 12% had cuff brachytherapy with chemotherapy (cuff/chemo), and 19% underwent pelvic radiation (EBRT). Complete RFS and OS data were available for 607 and 609 patients, respectively, and the median follow-up time was 58 months. As compared with patients who received no adjuvant therapy, patients who received cuff or cuff/chemo had improved RFS (cuff: HR 0.70, p = 0.02; cuff/chemo HR 0.53, p = 0.01) and OS (cuff HR 0.56, p = 0.001; cuff/chemo HR 0.48, p = 0.01). In a direct comparison, patients with cuff/chemo had better RFS and OS than those with chemotherapy alone (RFS HR 0.52, p = 0.03; OS HR 0.50, p = 0.05). There were no differences in RFS or OS for women who received chemotherapy alone or EBRT. Improved survival with cuff and cuff/chemo persisted on multivariable analyses (included age, stage, LVSI, adjuvant therapy type); additionally, EBRT was also associated with improved OS. In analyses limited to patients without myometrial invasion, patients with cuff or cuff/chemo had improved RFS and OS compared with observation alone. Conclusions: The use of adjuvant cuff brachytherapy with and without chemotherapy was associated with improved RFS and OS in patients with early stage uterine serous carcinoma.