biostudies-literatureBarr CECancer Research UKJon Moultin Charity TrustNational Institute for Health Research (NIHR)2834https://www.ebi.ac.uk/biostudies/studies/S-EPMC9689358biostudies-literatureUnknown12(11)Early detection of endometrial cancer improves survival. Non-invasive diagnostic biomarkers would improve triage of symptomatic women for investigations. This study aimed to determine the diagnostic accuracy of serum Cancer Antigen 125 (CA125) and Human Epididymis 4 (HE4) for endometrial cancer and associated high-risk features. Serum samples from women investigated for gynaecological symptoms or diagnosed with endometrial cancer were analysed for CA125 and HE4. Conventional diagnostic metrics were calculated. In total, 755 women were included; 397 had endometrial cancer. Serum CA125 and HE4 were significantly elevated in cases compared with controls (both <i>p</i> < 0.001), and with pathological markers of disease severity (<i>p</i> < 0.05). A combination of CA125 and HE4 detected eDiagnostics (Basel, Switzerland)Serum CA125 and HE4 as Biomarkers for the Detection of Endometrial Cancer and Associated High-Risk Features.PMC9689358C147/A25254NAIS-BRC-1215-20007NIHR300650Jones ERCrosbie EJNjoku KBarr CEfalseSerum CA125 and HE4 as Biomarkers for the Detection of Endometrial Cancer and Associated High-Risk Features.Early detection of endometrial cancer improves survival. Non-invasive diagnostic biomarkers would improve triage of symptomatic women for investigations. This study aimed to determine the diagnostic accuracy of serum Cancer Antigen 125 (CA125) and Human Epididymis 4 (HE4) for endometrial cancer and associated high-risk features. Serum samples from women investigated for gynaecological symptoms or diagnosed with endometrial cancer were analysed for CA125 and HE4. Conventional diagnostic metrics were calculated. In total, 755 women were included; 397 had endometrial cancer. Serum CA125 and HE4 were significantly elevated in cases compared with controls (both <i>p</i> < 0.001), and with pathological markers of disease severity (<i>p</i> < 0.05). A combination of CA125 and HE4 detected e2022-01-01T00:00:00Z2022 Nov2025-04-04T13:28:15.92Z2025-04-04T13:28:15.92ZS-EPMC96893583642889410.3390/diagnostics12112834