OBJECTIVE To compare the effects of intra-articular (IA) versus IV administration of morphine on local and systemic inflammatory responses in horses with experimentally induced acute synovitis. METHODS 8 horses. METHODS Each horse received the following 2 treatments 4 hours after synovitis was induced: IA administration of morphine (0.05 mg/kg) with IV administration of 1 mL of saline (0.9% NaCl) solution/100 kg, and IA administration of 1 mL of saline solution/100 kg with IV administration of morphine (0.05 mg/kg). Treatments were administered in randomized order with a washout period of 3 weeks between treatments. Before each treatment, aseptic synovitis was induced by injection of lipopolysaccharide into a radiocarpal joint. For the second treatment, the contralateral radiocarpal joint was selected. Joint swelling and skin temperature over the treated joints were recorded. Clinical examinations were performed, and blood WBC count, serum amyloid A (SAA) concentration, serum cortisol concentration, synovial fluid WBC count, synovial fluid total protein (TP) concentration, and synovial fluid SAA concentration were measured before and repeatedly during each of the two 168-hour study periods. Data were analyzed by use of ANOVA with repeated measures. RESULTS IA administration of morphine resulted in significantly less joint swelling and lower synovial fluid TP and serum and synovial fluid SAA concentrations, and blood WBC count than did IV administration of morphine. CONCLUSIONS IA administration of morphine exerted anti-inflammatory properties in horses with experimentally induced acute synovitis, supporting its use as a part of a balanced analgesic protocol.