This study sought to determine analgesic efficacy of liposomal hydromorphone (LE-hydro) in dogs undergoing limb amputation. LE-hydro has a 4-day release period and has been shown to provide adequate analgesia in dogs undergoing ovariohysterectomy at a dosage of 2 mg/kg subcutaneously (SC). In this study, 28 dogs presenting with primary sarcoma of appendicular bone requiring forelimb or hind-limb amputation were randomly divided into 3 treatment groups: (1) positive control: SC hydromorphone and blank SC liposomes before surgery, fentanyl CRI during and for 24 hours after surgery and a fentanyl patch at extubation; (2) negative control: hydromorphone and blank SC liposomes before surgery, fentanyl CRI during surgery only, and a fentanyl patch at extubation; and, (3) test group: SC LE-hydro and SC saline before surgery and saline CRI during and for 24 hours after surgery. All groups received SC carprofen and a bupivacaine block in the limb before surgery. Treatment failures, pain scores, opioid side effects, heart and respiratory rates, temperature, and client-reported pain and side effects were evaluated. Analgesic efficacy of the test-group was equal to the positive-control group and superior to the negative control group. There was a significant decrease in constipation in the LE-hydro group compared with the other 2 groups. The authors conclude that LE-hydro provides postoperative analgesia equivalent to fentanyl CRI in dogs undergoing limb amputation.