PURPOSE: To compare femoral cross-pin guidewire insertion at differing angles to identify "safe zones" relative to saphenous nerve, popliteus tendon, fibular collateral ligament, peroneal nerve, and femoral artery/vein locations between transtibial and medial-portal femoral tunnel drilling methods. METHODS: Five paired cadaveric knees were randomly assigned to a transtibial or medial-portal femoral (anatomic) tunnel drilling group. Guidewires were inserted at differing frontal plane angles (+10°, 0°, -10°, and -20°). Distances between the guidewire and the anatomic structure of interest were measured with an electronic caliper. RESULTS: Two-way analysis of variance showed that guidewire angle, not tunnel drilling method, created significant differences between guidewire-saphenous nerve (P < .001) and guidewire-femoral artery/vein (P < .001) distances. The +10° angle showed a shorter guidewire-saphenous nerve distance than the 0°, -10°, and -20° angles. The +10° angle also showed a shorter guidewire-femoral artery/vein distance than the -10° and -20° angles, and the 0° insertion angle created a shorter guidewire-femoral artery/vein distance than the -10° and -20° angles. Fisher exact tests showed that guidewires inserted at a +10° angle showed a greater incidence of safe-zone violations for the saphenous nerve (P = .04) and femoral artery/vein (P < .0001). CONCLUSIONS: Insertion angle, not tunnel drilling method, influenced saphenous nerve and femoral artery/vein injury risk. At the +10° angle, the saphenous nerve and femoral artery/vein are at greater risk for surgically induced injury. Guidewire insertion at -10° or -20° angles should increase concerns about potential popliteus tendon and fibular collateral ligament injury. CLINICAL RELEVANCE: Insertion angle, not tunnel drilling method, influenced saphenous nerve and femoral artery/vein injury risk.