Background <p>Accurate cellular dosimetry is essential to investigate fundamental mechanisms of targeted radionuclide therapy. The aim of this study was to assess how morphological cellular geometry models influence cellular dosimetry estimates, in comparison to simplified spherical models that do not properly represent an adherent cell geometry.</p> Methods <p>Virtual cell models of the CA20948 cell line were generated by confocal microscopy of SSTR2 and DAPI staining and served as input to derive morphological S-values for ¹⁷⁷Lu and ¹⁶¹Tb. Absorbed dose–response relationships were established for [¹⁷⁷Lu]Lu-DOTA-TATE, [¹⁶¹Tb]Tb-DOTA-TATE, [¹⁷⁷Lu]Lu-DOTA-LM3 and [¹⁶¹Tb]Tb-DOTA-LM3 using S-values from both morphological and spherical cell geometries.</p> Results <p>Thirty-four cell geometries were modeled and a spherical model with equivalent volume was generated with a radius for the cell and nucleus of 8.6(7) µm and 5.5(6) µm, respectively. Compared to spherical cell models, morphological cell models significantly changed the S-value with an increase of 13% (¹⁷⁷Lu) and 22% (¹⁶¹Tb) with the cell membrane as source region and a decrease of 11% (¹⁷⁷Lu) and 12% (¹⁶¹Tb) with the cytoplasm as source region. Absorbed dose-response relationships based on morphological cell geometries showed a linear dose-response model for [¹⁷⁷Lu]Lu-DOTA-TATE and [¹⁶¹Tb]Tb-DOTA-TATE with α = 0.22[0.18,0.26] Gy-1, and a linear-quadratic dose-response model for [¹⁷⁷Lu]Lu-DOTA-LM3 and [¹⁶¹Tb]Tb-DOTA-LM3 with α = 0.000[0.000,0.022] Gy-1 and β = 0.064[0.055,0.072] Gy-2. The assumption of a spherical cell model did not significantly affect the dose-response models, while underestimating the cell dimensions did induce a rescaling of the dose-response models.</p> Conclusion <p>These findings validate the use of simplified spherical models for CA20948 cells but highlight the importance of a correct estimation of the cell dimensions. </p>