An enzyme-linked immunosorbent assay was used to evaluate and compare the immunoglobulin G antibody response to Staphylococcus aureus cell walls of rabbits with either chronic staphylococcal osteomyelitis or subcutaneous abscesses. Osteomyelitis of the femur was produced by the intramedullary application of a sclerosing agent (3% sodium tetradecyl sulfate) and S. aureus. Radiographic evidence of osteomyelitis was observed in 10 of the 13 animals that survived the 10-week experimental period, and the diagnosis was confirmed by histopathology in 8 of the 10 instances. Abscess formation was initiated in a separate group of rabbits by the subcutaneous injection of S. aureus cells. All 10 of these rabbits subsequently developed abscesses, which usually resolved spontaneously within 3 to 5 weeks. Elevated levels of immunoglobulin G antibodies to the cell wall antigen were detected in 7 of 10 rabbits with osteomyelitis at 21 days postinfection, and these animals continued to display high antibody levels even at 59 days postinfection. In contrast, elevated levels of anti-cell-wall antibodies were only detected in 1 of 10 rabbits with subcutaneous abscesses. The enzyme-linked immunosorbent assay was found to be a rapid and sensitive serological technique for the detection of cell wall antibodies in this experimental osteomyelitis model and may be useful for the diagnosis of staphylococcal bone infections in humans.