OBJECTIVE To assess whether IV regional limb perfusion (IVRLP) and intraosseous regional limb perfusion (IORLP) of ceftiofur sodium resulted in clinically relevant drug concentrations in the synovial fluid of the tibiotarsal-tarsometatarsal joint of chickens (ie, an avian model) and to determine whether one of those techniques was superior to the other. ANIMALS 12 healthy adult hens. PROCEDURES Birds were randomly assigned to receive ceftiofur sodium (2 mg/kg) by the IVRLP (n = 4), IORLP (4), or IM (control; 4) route once daily for 6 consecutive days. Blood and tibiotarsal-tarsometatarsal synovial fluid samples were collected 15 minutes after ceftiofur administration on predetermined days for quantification of ceftiofur concentration. Plasma and synovial fluid ceftiofur concentrations were compared among the 3 groups. RESULTS All 4 birds in the IVRLP group developed mild to moderate bruising around the injection site, but this bruising did not prohibit completion of the prescribed treatment regimen. No adverse effects were observed in any of the other birds. The mean plasma and synovial fluid ceftiofur concentrations exceeded the therapeutic threshold for most common bacterial pathogens (> 1.0 μg/mL) at all sample acquisition times for all 3 groups. The mean synovial fluid ceftiofur concentration for the IVRLP group was significantly greater than that for the IORLP and control groups at all sample acquisition times. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that IVRLP may be a safe and effective technique for antimicrobial administration to birds with joint infections, contaminated wounds, pododermatitis, and other musculoskeletal infections of the distal aspect of a limb.