To assess the performance of simultaneous endometrial aspiration and sonohysterography to screen for endometrial cancer or hyperplasia in women aged 50 years or older. We conducted a prospective study from February 2014 to October 2020 at the ultrasound unit of a large urban academic medical center. The study included 1,635 women aged 50 years or older referred for endometrial evaluation, with follow-up through January 2021. Participants underwent saline infusion sonohysterography combined with ultrasound-guided endometrial aspiration. The primary outcome measured was a diagnosis of endometrial cancer or hyperplasia within 1 year from screening. The diagnostic accuracy of the combined evaluation method, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), was assessed. Of 1,170 women who completed the study protocol, 82 (7.0%) had endometrial cancer and 42 (3.6%) had endometrial hyperplasia. Of all patients who developed cancer during the follow-up period, 85.5% were diagnosed within 1 year after evaluation. The application of simultaneous endometrial aspiration and sonohysterography together demonstrated a sensitivity of 99.1%, specificity of 24.9%, PPV of 11.8%, and NPV of 99.6%. Using a theoretical sequential approach, assuming an endometrial aspiration is performed only in patients determined to be high risk by sonohysterography, demonstrated a sensitivity of 93.4%, specificity of 99.9%, PPV of 99.0%, and NPV of 99.3%. Simultaneous endometrial aspiration and sonohysterography is an effective one-stop outpatient screening tool for detecting endometrial cancer and hyperplasia in women aged 50 years or older. With the integration of two screening modalities into a single procedure, simultaneous endometrial aspiration and sonohysterography may overcome the limitations inherent in each of the currently recommended methods individually, potentially improving patient prognosis and streamlining the diagnostic process.