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Purpose: The main objective of this study was to evaluate the ability of a large field Cadmium Zinc Telluride (CZT) camera to estimate thyroid uptake (TU) on single photon emission computed tomography (SPECT) images with and without attenuation correction (Tomo-AC and Tomo-NoAC) compared with Planar acquisition in a series of 23 consecutive patients. The secondary objective was to determine radiation doses for the tracer administration and for the additional Computed Tomography (CT) scan. Methods: Cross-calibration factors were determined using a thyroid phantom, for Planar, Tomo-AC and Tomo-NoAC images. Then Planar and SPECT/CT acquisitions centered on the thyroid were performed on 5 anthropomorphic phantoms with activity ranging from 0.4 to 10 MBq, and 23 patients after administration of 79.2 ± 3.7 MBq of [99mTc]-pertechnetate. We estimated the absolute thyroid activity (AThA) for the anthropomorphic phantoms and the TU for the patients. Radiation dose was also determined using International Commission on Radiological Protection (ICRP) reports and VirtualDoseTMCT software. Results: Cross-calibration factors were 66.2 ± 4.9, 60.7 ± 0.7 and 26.5 ± 0.3 counts/(MBq s), respectively, for Planar, Tomo-AC and Tomo-NoAC images. Theoretical and estimated AThA for Planar, Tomo-AC and Tomo-NoAC images were statistically highly correlated (r < 0.99; P < 10–4) and the average of the relative percentage difference between theoretical and estimated AThA were (8.6 ± 17.8), (− 1.3 ± 5.2) and (12.8 ± 5.7) %, respectively. Comparisons between TU based on different pairs of images (Planar vs Tomo-AC, Planar vs Tomo-NoAC and Tomo-AC vs Tomo-NoAC) showed statistically significant correlation (r = 0.972, 0.961 and 0.935, respectively; P < 10–3). Effective and thyroid absorbed doses were, respectively (0.34CT + 0.95NM) mSv, and (3.88CT + 1.74NM) mGy. Conclusion: AThA estimation using Planar and SPECT/CT acquisitions on a new generation of CZT large-field cameras is feasible. In addition, TU on SPECT/CT was as accurate as conventional planar acquisition, but the CT induced additional thyroid exposure. Trial registration Name of the registry: Thyroid Uptake Quantification on a New Generation of Gamma Camera (QUANTHYC). Trial number: NCT05049551. Registered September 20, 2021—Retrospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT05049551?cntry=MC&draw=2&rank=4. [ABSTRACT FROM AUTHOR]