Background and Objectives: Major ankle surgery causes intense postoperative pain, and whereas the importance of a sciatic nerve block is well established, the clinical significance of a supplemental saphenous nerve block has never been determined in a prospective, randomized, double-blind, placebo-controlled trial. We hypothesized that a saphenous nerve block reduces the proportion of patients experiencing significant clinical pain after major ankle surgery. Methods: Eighteen patients were enrolled and received a popliteal sciatic nerve block. Patients were randomized to single-injection saphenous nerve block with 10 mL 0.5% bupivacaine with 1:200,000 epinephrine or 10 mL saline (Fig. 1). Primary outcome was the proportion of patients reporting significant clinical pain, defined as a score greater than 3 on the numerical rating scale. Secondary outcomes were maximal pain and analgesia of the cutaneous territory of the infrapatellar branch of the saphenous nerve. Results: Eight of 9 patients in the placebo group reported significant clinical pain versus 1 of 9 patients in the bupivacaine-epinephrine group (P = 0.003). Maximal pain was significantly lower in the active compared with the placebo group (median, 0 [0-0] vs 5 [4-6]; P = 0.001). Breakthrough pain from the saphenous territory began within 30 minutes after surgery in all cases. Sensory testing of the cutaneous territory of the infrapatellar branch of the saphenous nerve showed correlation between pain reported in the anteromedial ankle region and the intensity of cutaneous sensory block in the anteromedial knee region. Conclusions: The saphenous nerve is an important contributor to postoperative pain after major ankle surgery, with significant clinical pain appearing within 30 minutes after surgery.