Objectives <p>To evaluate the diagnostic value of four-dimensional computed tomography (4DCT) in conjunction with ultrasonography (US) and sestamibi scintigraphy (SeS) with ^99mTc-MIBI, compared to US and SeS alone in primary hyperparathyroidism.</p> Materials and methods <p>A retrospective study was conducted on patients who underwent 4DCT for suspected parathyroid adenomas between January 2019 and December 2023, followed by surgical exploration. The diagnostic performance of 4DCT, US, and SeS was compared in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. Additionally, enhancement patterns, false-negative and false-positive 4DCT results, and adenoma location in cases with negative US and SeS findings were analyzed.</p> Results <p>One hundred forty-six 4DCT studies were included. Overall, adding 4DCT to US and/or SeS demonstrated significantly higher sensitivity (76.4%) and accuracy (75.7%) compared to US (31.8% and 35.7%) and SeS (26.2% and 31.6%) alone. Specificity was highest for SeS (85.7%), followed by 4DCT (78.3%) and US (72.5%). PPV was high for all modalities, with 4DCT achieving 96.1%, while NPV was low (22.4% for 4DCT, 9.8% for US, 10.3% for SeS). False-negative 4DCT results were mostly due to adenoma adherence to the thyroid. 4DCT identified 48 adenomas missed by US and SeS, with 21 located in ectopic sites.</p> Conclusion <p>Adding 4DCT to US and/or SeS provides superior sensitivity and accuracy in detecting parathyroid adenomas compared to US and SeS alone. However, negative results should be interpreted cautiously in patients with clinical and biochemical suspicion for primary hyperparathyroidism.</p> Critical relevance statement <p>Adding 4DCT to US and SeS offers superior sensitivity and accuracy in detecting parathyroid adenomas, potentially enhancing clinical decision-making—particularly in challenging cases where prior imaging was negative—though negative results should be interpreted with caution.</p> Key Points <p><UnorderedList Mark="Bullet"> <ItemContent> <p>Adding 4D-CT to US and sestamibi scintigraphy (SeS) significantly improves the detection of parathyroid adenomas over US and SeS alone.</p> </ItemContent> <ItemContent> <p>4D-CT provides the highest agreement with surgical findings, improving surgical planning.</p> </ItemContent> <ItemContent> <p>4D-CT effectively identifies adenomas in ectopic locations, often missed by US and SeS.</p> </ItemContent> <ItemContent> <p>The most common cause of false-negative 4D-CT results is adenoma adherence to the thyroid, misread as thyroid tissue.</p> </ItemContent> <ItemContent> <p>Negative imaging results across all modalities warrant cautious interpretation.</p> </ItemContent> </UnorderedList></p> Graphical Abstract <p></p>