Purpose <p>To evaluate technical success, diagnostic yield, and complication rates of image-guided percutaneous splenic biopsies based on multicenter registry data from the German Society for Interventional Radiology and Minimally Invasive Therapy.</p> Materials and Methods <p>This retrospective multicenter study analyzed image-guided percutaneous splenic biopsies documented in the prospective DeGIR registry between 2018 and 2024. Technical success was defined as needle placement within the target lesion. Diagnostic yield was defined as histologically adequate samples enabling clinical diagnosis.</p> Results <p>Four hundred splenic biopsies from 92 centers were included. Technical success was achieved in 99.00% of procedures. The complication rate was 5.00%, including 2.50% major complications with no procedure-related deaths. Complication rates were higher for procedures performed under local anesthesia than analgesic sedation (<i>p</i> = 0.042).</p> <p>Histopathological reports were available for 338 procedures, resulting in a diagnostic yield of 90.83%. Diagnostic yield increased with the number of biopsy samples, reaching a maximum with three samples. Procedures performed under analgesic sedation showed a higher diagnostic yield than those under local anesthesia (<i>p</i> = 0.019).</p> Conclusion <p>Image-guided percutaneous splenic biopsy is a safe and effective diagnostic procedure with high technical success and diagnostic yield. Analgesic sedation and obtaining up to three biopsy samples may improve diagnostic performance without increasing complication rates.</p> Graphical Abstract <p></p>