Advance 3D quantitative radionuclide imaging techniques boost the accuracy of targeted radionuclide therapy (TRT) dosimetry to voxel level. The goal of this work is to develop a comprehensive 3D dosimetric software, BIGDOSE, with new features of image registration and virtual CT for patient-specific dosimetry.BIGDOSE includes a portable graphical user interface written in Python, integrating (I) input of sequential ECT/CT images; (II) segmentation; (III) non-rigid image registration; (IV) curve fitting and voxel-based integration; (V) dose conversion and (VI) 3D dose analysis. The accuracy of the software was evaluated using a simulation study with 9 XCAT phantoms. We simulated SPECT/CT acquisitions at 1, 12, 24, 72 and 144-hrs post In-111 Zevalin injection with inter-scans misalignments using an analytical projector for medium energy general purpose (MEGP) collimator, modeling attenuation, scatter and collimator-detector response. The SPECT data were reconstructed using quantitative OS-EM method. A CT organ-based registration was performed before the dose calculation. Organ absorbed doses for the corresponding Y-90 therapeutic agent were calculated on target organs and compared with those obtained from OLINDA/EXM, using dose measured from GATE as the gold standard. One patient with In-111 DTPAOC injection as well as two patients with Y-90 microsphere embolization were used to demonstrate the clinical effectiveness of our software.In the simulation, the organ dose errors of BIGDOSE were -9.59%±9.06%, -8.36±5.82%, -23.41%±6.67%, -6.05%±2.06% for liver, spleen, kidneys and lungs, while they were -25.72%±12.52%, -14.93%±10.91%, -28.63%±12.97% and -45.30%±5.84% for OLINDA/EXM. Cumulative dose volume histograms, dose maps and iso-dose contours provided 3D dose distribution information on the simulated and patient data.BIGDOSE provides a one-stop platform for voxel-based dose estimation with enhanced functions. It is a promising tool to streamline the current clinical TRT dosimetric practice with high accuracy, incorporating 3D personalized imaging information for improved treatment outcome.