© 2014, Society of Surgical Oncology. Background: Four-dimensional computed tomography (4D CT) has emerged as an extremely sensitive preoperative imaging modality for primary hyperparathyroidism compared with the historical use of sestamibi and ultrasound (US). Specialized volume rendering and technical modifications further enhance this technique for operative guidance while reducing radiation exposure.Methods: Patients undergoing parathyroidectomy for primary hyperparathyroidism from December 2010 to September 2013, carried out by two surgeons at a tertiary cancer center, were evaluated. Comparison was made between the three imaging modalities (4D CT, sestamibi, and US) for preoperative localization rate and accuracy. Biochemical parameters and radiation exposure were also analyzed.Results: A total of 202 patients were identified from the database and 200 patients were included in the analysis. All patients underwent 4D CT (100 %), 185 sestamibi (92.5 %) and 186 US (93 %). In patients with single-gland disease (n = 153), 4D CT, sestamibi, and US were positive in 96 %, 65.4 % and 57.7 % of patients, respectively and, when positive, were accurately localized in 97.2 %, 93.4 % and 96.3 % of patients, respectively. In patients with multigland disease (MGD) [n = 47], 4D CT, sestamibi, and US predicted MGD in 32 %, 0 %, and 13.6 % of patients, respectively. With our technique modification, radiation exposure from 4D CT approached that of sestamibi.Conclusions: Low-dose, modified 4D CT with volume rendering when compared with sestamibi has a statistically significant higher positivity rate, improved accuracy rate, provides excellent images, superior surgical planning, and has a comparable radiation exposure risk profile. Consideration should be made for the abandonment of routine sestamibi single-positron emission computed tomography (SPECT), with 4D CT as the preoperative imaging modality of choice.