Our lab has developed a slow-release liposomal formulation of oxymorphone (LEOx). The purpose of this study was to compare sedative effects and serum concentrations of oxymorphone after administration of LEOx and standard oxymorphone (STDOx) to dogs. At baseline, 1 mL of blood was drawn from the cephalic vein and sedation score was recorded. Dogs were divided into four groups (n = 6): (i) LEOx 1.0 mg kg–1; (ii) LEOx 0.5 mg kg–1; (iii) STDOx 0.1 mg kg–1; (iv) STDOx 0.05 mg kg–1. Unloaded liposomal vehicle (0.5 mL) was used as a control (n = 2). All treatments were given subcutaneously between the scapulae. Sedation score and serum concentration of drug were recorded at 0.5, 1, 2, 4, 8, 12, 16, 24 hours and daily for 5 days. Serum concentrations were measured with ELISA. At all time points, drug was not detected and sedation score was 0 in the control group. Sedation score for group 1 was significantly higher (p < 0.05) at 1 hour than for groups 2,3, and 4. There was no difference in sedation score between treatment groups at any other time. Serum concentrations of drug were significantly higher (p < 0.05) for group 1 at all time points measured after baseline. In groups 2, 3, and 4, serum concentrations of drug fell below the limit of detection (1.5 ng mL–1) by 24 hours. Serum concentrations after 0.1 mg kg–1of STDOx were 11.1 ± 3.6 ng mL–1at 4 hours, which is the recommended time for redosing and presumably reflects the lower end of a therapeutic serum concentration. Serum concentrations were comparable after 1.0 mg kg–1 of LEOx (10.5 ± 2.4 ng mL–1) 48 hours after administration. These results suggest that liposomal oxymorphone may provide therapeutic serum concentrations of drug for 2 days after a single subcutaneous administration without undue sedation or other deleterious effects in healthy dogs. Further studies are warranted to assess analgesic efficacy and pharmacokinetics of lipsomal oxymorphone in dogs.