Purpose Voxel‐based dosimetry is potentially accurate than organ‐based dosimetry because it considers the anatomical variations in each individual and the heterogeneous radioactivity distribution in each organ. Here, voxel‐based dosimetry for 177Lu‐DOTATATE therapy was performed using single and multiple voxel S‐value (VSV) methods and compared with Monte Carlo simulations. To verify these methods, we adopted sequential 177Lu‐DOTATATE single‐photon emission computed tomography and X‐ray computed tomography (SPECT/CT) dataset acquired from Sunway Medical Centre using the major vendor's SPECT/CT scanner (Siemens Symbia Intevo). Methods The administered activity of 177Lu‐DOTATATE was 7.99 ± 0.36 GBq. SPECT/CT images were acquired 0.5, 4, 24, and 48 h after injection in Sunway Medical Centre. For the multiple VSV method, VSV kernels of 177Lu in media with various densities were generated by Geant4 Application for Emission Tomography (GATE) simulation first. The second step involved the convolution of the time‐integrated activity map with each kernel to produce medium‐specific dose maps. Third, each medium‐specific dose map was masked using binary medium masks, which were generated from CT‐based density maps. Finally, all masked dose maps were summed to generate the final dose map. VSV methods with four different VSV sets (1, 4, 10, and 20 VSVs) were compared. Voxel‐wise density correction for the single VSV method was also performed. The absorbed doses in the kidneys, bone marrow, and tumors were analyzed, and the relative errors between the VSV and Monte Carlo simulation approaches were estimated. Organ‐based dosimetry using Organ Level INternal Dose Assessment/EXponential Modeling (OLINDA/EXM) was also compared. Results The accuracy of the multiple VSV approach increased with the number of dose kernels. The average dose estimation errors of a single VSV with density correction and 20 VSVs were less than 6% in most cases, although organ‐based dosimetry using OLINDA/EXM yielded an error of up to 123%. The advantages of the single VSV method with density correction and the 20 VSVs over organ‐based dosimetry were most evident in bone marrow and bone‐metastatic tumors with heterogeneous medium properties. Conclusion The single VSV method with density correction and multiple VSV method with 20 dose kernels enabled fast and accurate radiation dose estimation. Accordingly, voxel‐based dosimetry methods can be useful for managing administration activity and for investigating tumor dose responses to further increase the therapeutic efficacy of 177Lu‐DOTATATE.

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