Objective: To compare clinical outcomes of patients with early-stage, high-intermediate risk (HIR) endometrial cancer (EC) and isolated tumor cells (ITC) lymph node metastases treated with chemotherapy/radiotherapy (CRT) vs. external beam radiotherapy (EBRT)/vaginal brachytherapy (VBT). Methods: We retrospectively identified all patients with early-stage HIR endometrioid EC and ITC treated with CRT or EBRT from our institutional database (January-2015 to December-2023). All patients underwent sentinel lymph node (SLN) assessments per NCCN guidelines. Progression-free survival (PFS) and cancer specific survival (CSS) were analyzed using Kaplan-Meier method. We utilized a GOG-99 scoring system in the HIR-ITC cohort to assess risk factors for recurrence. Results: 48 patients were identified, 32(67 %) treated with CRT, 15(31 %) with EBRT and 1(2 %) with VBT alone. Median follow-up was 63.2 and 28 months in CRT vs EBRT/VBT, respectively (p = 0.001). In CRT cohort, 4(12.5 %) recurred; two patients with isolated lung metastasis were salvaged and two with multiple sites of metastasis died with disease. No patient in EBRT/VBT cohort (n = 16) recurred. Estimated PFS were 84.4 % and 100 % for CRT and EBRT/VBT, respectively (p = 0.392), and CSS were 93.7 % vs. 100 %, respectively (p = 0.457). Using HIR scoring per GOG-99, 21(66 %) patients in CRT cohort had three or more HIR risk factors and 4(19 %) recurred despite adjuvant therapy. Conclusion: In this retrospective study, there was no significant difference in survival for patients with HIR endometrial cancer and ITC SLNs treated with either EBRT/VBT or CRT. Patients with three or more HIR risk factors remain at risk for recurrence despite CRT. Further prospective studies should assess recurrence risk factors in HIR EC with ITC, likely incorporating standard histopathology and molecular profiles to tailor adjuvant CRT.