Background <p>Percutaneous nephrolithotomy (PCNL) is the standard treatment for large or complex renal stones; however, it carries risks such as bleeding and venous thromboembolism (VTE). Current guidelines do not recommend routine pharmacologic thromboprophylaxis in these patients due to concerns about bleeding and limited supporting evidence. This study evaluates the safety and efficacy of unfractionated heparin thromboprophylaxis in patients at moderate to high VTE risk undergoing PCNL.</p> Methods <p>In this retrospective cohort study, 202 patients undergoing PCNL were assigned to either heparin prophylaxis (<i>n</i> = 79) or early ambulation without pharmacologic prophylaxis (<i>n</i> = 123). Baseline demographics, stone characteristics, operative parameters, and postoperative outcomes—including bleeding, transfusion, complications, hemoglobin drop, and thromboembolic events were compared.</p> Results <p>Patients receiving heparin were older (55.1 vs. 44.5 years, <i>p</i> &lt; 0.001) and had higher BMI (median 28.9 vs. 26.5&#xa0;kg/m², <i>p</i> = 0.001). No significant differences were observed in stone size, location, surgery duration, hemoglobin drop, transfusion rates, or overall complications. Access tract length was slightly longer in the heparin group (<i>p</i> = 0.028). Thromboembolic events were rare and did not differ significantly between groups (<i>p</i> = 0.282). Notably, in the early ambulation group, one patient experienced deep vein thrombosis and two developed pulmonary thromboembolism (one fatal).</p> Conclusions <p>Pharmacologic thromboprophylaxis with unfractionated heparin after PCNL appears safe without increased bleeding risk. While our findings suggest a potential benefit in reducing thromboembolic events in moderate- to high-risk patients, the limited sample size and retrospective design preclude definitive conclusions.</p>