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General anesthesia for breast surgery may be supplemented by using a regional anesthetic technique. We evaluated the efficacy of the first pectoral nerve block (Pecs I) in treating postoperative pain after breast cancer surgery.A randomized, double-blind, dual-centered, placebo-controlled trial was performed. One hundred twenty-eight patients scheduled for unilateral breast cancer surgery were recruited. A multimodal analgesic regimen and surgeon-administered local anesthetic infiltration were used for all patients. Ultrasound-guided Pecs I was performed using bupivacaine or saline. The primary outcome was the patient pain score (numerical rating scale [NRS]) in the recovery unit 30 minutes after admission or just before the morphine administration (NRS ≥4/10). The secondary outcomes were postoperative opioid consumption (ie, in the recovery unit and after 24 hours).During recovery, no significant difference in NRS was observed between the bupivacaine (n = 62, 3.0 [1.0–4.0]) and placebo (n = 65, 3.0 [1.0–5.0]) groups (P = 0.55). However, the NRS was statistically significantly different, although not clinically significant, for patients undergoing major surgeries (mastectomies or tumorectomies with axillary clearance) (n = 29, 3.0 [0.0–4.0] vs 4.0 [2.0–5.0], P = 0.04). Morphine consumption during recovery did not differ (1.5 mg [0.0–6.0 mg] vs 3.0 mg [0.0–6.0 mg], P = 0.20), except in the major surgery subgroup (1.5 mg [0.0–6.0 mg] vs 6.0 mg [0.0–12.0 mg], P = 0.016). Intraoperative sufentanil and cumulative morphine consumption up to 24 hours did not differ between the 2 groups. Three patients experienced complications related to the Pecs I.Pecs I is not better than a saline placebo in the presence of multimodal analgesia for breast cancer surgery. However, its role in extended (major) breast surgery may warrant further investigation.This study was registered at ClinicalTrials.gov, identifier NCT01670448.