Background: Women with high-risk endometrial cancer (HREC) are at increased risk of distant metastasis and endometrial cancer-related death. The randomized PORTEC-3 intergroup trial was initiated to investigate the benefit of adjuvant chemotherapy during and after radiotherapy (CTRT) versus pelvic radiotherapy (RT) alone for women with HREC. Methods: Women with HREC (FIGO stage I grade 3 with deep myometrial invasion and/or LVSI; stage II or III; or serous/clear cell histology) were randomly allocated (1:1) to RT (48.6 Gy in 1.8 Gy fractions) or CTRT (two cycles of cisplatin 50 mg/m² in week 1 and 4 of RT, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m² at 3-week intervals) with stratification for participating center, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival (OS) and failure-free survival (FFS). The Kaplan-Meier method, log-rank test and Cox regression analysis were used for final analysis according to intention-to-treat. PORTEC-3 is registered with ISRCTN (ISRCTN14387080) and ClinicalTrials.gov (NCT00411138). Results: 686 women were enrolled between 2006 and 2013. 26 women were excluded; 13 withdrew consent early and 13 were ineligible, which left 660 patients in the analysis, with a median follow up time of 60.2 months (IQR 47.1–72.9): 330 CTRT and 330 RT. Three- and five-year OS for CTRT vs. RT was 84.4% versus 83.9%, and 81.8% versus 76.7%; overall HR 0.79 [95% CI 0.57-1.12, p=0.183]. Three-year FFS was 79.7% (CTRT) versus 71.8% (RT), and at 5 years 75.5% versus 68.9%, overall HR for FFS 0.77 [0.58-1.03, p=0.078]. Patients with stage III EC had lower 5-year FFS and OS compared to stage I-II (FFS 63.9% vs 78.9%, p<0.001, and OS 74.3% vs 83.1%, p=0.003). They also had greatest benefit of CTRT: 5-year FFS for stage III was 69.3% for CTRT vs 58.0% for RT [95% CI 0.45-0.97, p=0.032], and 5-year OS for stage III was 78.7 % vs 69.8% (p=0.114). Conclusions: Adjuvant chemotherapy given during and after pelvic radiotherapy for treatment of HREC did not significantly improve 5-year FFS and OS, compared with RT alone. For women with stage III EC FFS was however significantly improved with CTRT by 11% at 5 years. Follow-up will continue to evaluate long-term outcomes. Clinical trial information: NCT00411138