DepoFoam® bupivacaine (Pacira Pharmaceuticals, Inc., San Diego, CA, USA), an extended-release liposomal bupivacaine-based analgesic, was compared with placebo for the prevention of pain after bunionectomy in a randomized, multicenter, double-blind phase 3 clinical study. Patients received placebo (n = 96) or DepoFoam bupivacaine 120 mg (n = 97) via wound infiltration prior to closure. Pain intensity was assessed using a numeric rating scale (NRS) from time 0 through to 72 hours postsurgically. The primary efficacy measure was area under the curve (AUC) of NRS scores through 24 hours. Other efficacy measures included AUC of NRS at other time points, proportion of patients who were pain-free, time to first opioid use, and total postsurgical consumption of supplemental opioid medication. Adverse events were also assessed. The AUC for NRS scores was significantly less in patients treated with DepoFoam bupivacaine versus patients receiving placebo at 24 hours (P = 0.0005) and 36 hours (P < 0.0229). More patients treated with DepoFoam bupivacaine avoided use of opioid rescue medication during the first 24 hours (7.2% vs. 1%; P < 0.0404) and were pain-free (NRS ≤ 1) at 2, 4, 8, and 48 hours. Median time-to-first-opioid use was delayed in favor of DepoFoam bupivacaine (4.3 vs. 7.2 hours; P < 0.0001). Fewer adverse events were reported by patients treated with DepoFoam bupivacaine (59.8%) versus placebo (67.7%). DepoFoam bupivacaine, a long-acting local analgesic, provided extended pain relief and decreased opioid use after bunionectomy, compared with placebo.