Transarterial radioembolization using holmium-166 microspheres is a promising treatment for primary and secondary liver malignancies. Accurate post-therapeutic dosimetry is critical for optimizing outcomes, particularly in voxel-based dose assessment using quantitative single-photon emission computed tomography/ computed tomography (SPECT/CT). This study aimed to evaluate the impact of software choice and calibration method on absorbed dose estimates to the liver and tumor, by comparing two advanced dosimetry platforms: Hermia Voxel Dosimetry™ and Q-Suite™. Despite the recent discontinuation of ¹⁶⁶Ho-microsphere production, such studies remain highly relevant given the global emphasis on personalized dosimetry, quantitative imaging in nuclear medicine, and potential applicability to other therapeutic radiopharmaceuticals and future microsphere technologies. Fourteen patients underwent a scout procedure, followed by therapy and post-treatment SPECT/CT imaging. Initial analysis revealed substantially lower mean liver and tumor doses with Hermia (12 ± 4 Gy and 58 ± 23 Gy) compared to Q-Suite (44 ± 9 Gy and 209 ± 83 Gy), with statistically significant differences (p=0.002 and p<0.001). Discrepancies were due to the gamma camera dead time and Hermia’s fixed calibration factor (CF). A patient-specific CF, derived from the camera’s response curve and administered activity, was applied to correct Hermia dose maps. The corrected doses, 42 ± 6 Gy and 196 ± 17 Gy, closely matched those from Q-Suite (p=0.69 and p=0.64). These findings underscore the critical role of system-specific calibration and acquisition timing in achieving accurate voxel-based dosimetry. Underestimation of absorbed doses may lead to suboptimal clinical decisions, including undertreatment or unrecognized toxicity. Thus, implementing patient-specific calibration protocols or equivalent corrections for dead time is essential to support safe, consistent, and effective radionuclide therapy in clinical practice.