Purpose <p>Positron range correction (PRC) can mitigate the effect of the larger positron range on the image quality of Gallium-68 (⁶⁸Ga) PET-imaging. The aim of this study is to evaluate the improvement in ⁶⁸Ga-PET image quality by applying a tissue-dependent and spatially-variant PRC (TDSV PRC) for ⁶⁸Ga in a clinical setting.</p> Methods <p>A TDSV PRC technique was developed employing CT-driven segmentation masks of different tissue types (soft tissue, bone, lung) and the corresponding tissue-specific positron range kernels. OSEM reconstructions were performed using the proposed TDSV PRC, a tissue-independent PRC, and without any PRC (non-PRC). For lesions identified in [⁶⁸Ga]Ga-DOTATOC or [⁶⁸Ga]Ga-PSMA PET/CT data from 20 patients, the maximum standardized uptake value (SUV_max) and contrast-to-noise ratio (CNR) of this technique was compared to tissue-independent PRC and non-PRC images.</p> Results <p>A total of 93 lesions were analyzed (48 soft tissue, 35 bone, 10 lung lesions). For soft tissue lesions, TDSV and tissue-independent PRC showed similar increases in SUV_max (13.7%, <i>p</i> &lt; 0.001 vs. 13.6%, <i>p</i> &lt; 0.001) and CNR (11.0%, <i>p</i> &lt; 0.001 vs. 11.1%, <i>p</i> &lt; 0.001) compared to non-PRC. For bone lesions,&#xa0;tissue-independent PRC showed slightly higher not statistically significant increases than TDSV PRC in SUV_max (18.6%, <i>p</i> &lt; 0.001 vs. 17.4%, <i>p</i> &lt; 0.001) and CNR (14.6%, <i>p</i> &lt; 0.001 vs. 13.8%, <i>p</i> &lt; 0.001). In lung lesions, TDSV PRC increased SUV_max and CNR compared to non-PRC (SUV_max: 57.9%, <i>p</i> = 0.012; CNR: 43.9%, <i>p</i> = 0.012) and tissue-independent PRC (SUV_max: 46.0%, <i>p</i> = 0.012; CNR: 32.5%, <i>p</i> = 0.012).</p> Conclusion <p>TDSV PRC for ⁶⁸Ga PET/CT demonstrated to be feasible in clinical patient data, showing the greatest benefits for lung lesions.</p>