Purpose To review a single-center experience with the cortical tangential approach during computed tomography (CT)-guided native medical renal biopsy and to evaluate its efficacy and safety compared with those of a non-cortical tangential approach. Materials and Methods This retrospective study received institutional review board approval, with a waiver of the HIPAA requirement for informed consent. The number of cores, glomeruli, and complications were reviewed in 431 CT-guided medical renal biopsies performed between July 2007 and September 2015. A biopsy followed a cortical tangential approach if the needle path was parallel to the renal cortical surface, at a depth closer to the renal capsule than the renal pelvic fat. A sample was considered adequate if the biopsy yielded at least 10 glomeruli at light microscopy, one glomerulus at immunofluorescence microscopy, and one glomerulus at electron microscopy. The χ test, the t test, the Mann-Whitney test, and logistic regression modeling of sample adequacy were performed. Results One hundred fifty-six (36%) of 431 biopsies were performed with the cortical tangential approach. More cores were obtained for the cortical tangential group (2.6 vs 2.4, P = .001); biopsy needle gauge was not significantly different (P = .076). More adequate samples were obtained in the cortical tangential group (66.7% vs 49.8%, P = .001), with more glomeruli (23 vs 16, P = .014). Results were significant after controlling for needle gauge and number of cores (P = .008). The cortical tangential group had fewer complications (1.9% vs 7.3%, P = .018). Conclusion The cortical tangential approach, when applied to CT-guided native medical renal biopsies, results in higher rates of sample adequacy and lower rates of postprocedural complications. RSNA, 2016.