This randomized, active-controlled study evaluated the extent and duration of analgesia after administration of liposome bupivacaine (LB), a novel formulation of bupivacaine, compared with bupivacaine HCl given via local infiltration in excisional hemorrhoidectomy. One hundred patients were randomly assigned to receive a single dose of bupivacaine HCl 75 mg (0.25% with 1:200,000 epinephrine) or LB 66, 199, or 266 mg upon completion of hemorrhoidectomy. Postoperative pain intensity was assessed using a numeric rating scale at rest to calculate a cumulative pain score (area under the curve). Cumulative pain scores were significantly lower with LB at each study dose (P < 0.05) compared with bupivacaine HCl 72 hours after surgery. Post hoc analysis showed that mean total postoperative opioid consumption was statistically significantly lower for the LB 266-mg group compared with the bupivacaine HCl group during the 12- to 72-hour postoperative period (P = 0.019). Median time to first opioid use was 19 hours for LB 266 mg versus 8 hours for bupivacaine HCl (P = 0.005). Incidence of opioid-related adverse events was 4 per cent for LB 266 mg compared with 35 per cent for bupivacaine HCl (P = 0.007). Local infiltration with LB resulted in significantly reduced postsurgical pain compared with bupivacaine HCl in patients after hemorrhoidectomy surgery.