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Blockade of the sciatic nerve is necessary for complete analgesia of the lower extremity using peripheral nerve blocks. We identified the sciatic nerve in relation to the ischial tuberosity in fresh cadaver dissections as well as in patients to compare sciatic nerve blockade using the conventional approach versus our experimental approach. Specifically, we tested the hypothesis that in patients in the prone position, our novel approach (changing the point of needle insertion to 3 cm lateral from the ischial tuberosity) requires fewer needle passes and less time.The location of the sciatic nerve in relation to the ischial tuberosity was identified in 20 cadavers; this information was used to devise an alternative approach to the sciatic nerve. In a randomized, controlled, crossover patient study, we compared a prone subgluteal approach (conventional approach, n = 19) with an experimental approach with the insertion point 3 cm lateral to the midpoint of ischial tuberosity with patients in prone position (n = 20). We recorded the number of passes and the time taken to obtain an initial sciatic nerve twitch at a current of 1.5 mA and a twitch at <0.5 mA.The sciatic nerve averaged 2.8 ± 0.4 cm from the midpoint of ischial tuberosity in cadavers in prone position. When needles were inserted from surface landmarks, those inserted through the experimental insertion point consistently transected the sciatic nerve. In contrast, needles inserted through the conventional approach were 2.27 ± 0.47 cm lateral to the sciatic nerve. Clinically, our experimental approach required fewer passes to obtain a sciatic nerve twitch than the conventional approach. We were unable to obtain a twitch in 55% of patients with the conventional approach and converted them to the experimental approach. In patients originally assigned to the experimental approach and those switched to the experimental approach after failure with the conventional approach, we obtained the first sciatic nerve twitch in 1 pass in 45% of the patients and in 3 passes in 85%.We describe a landmark that is more effective for identifying the location of the sciatic nerve than that used for the prone subgluteal approach.