Twenty-two adult diabetic patients with clinical suspicion of foot and/or ankle infection were prospectively evaluated using radiography, technetium-99m methylene diphosphonate bone scanning (99mTc), indium-111-labeled leukocyte scanning (111In), and gallium-67 scanning (67Ga) to determine the presence of clinically suspected osteomyelitis. Biopsy for culture and histology was performed in 16 patients. The diagnosis of osteomyelitis was confirmed by biopsy in 12 patients. The remaining 10 patients had no evidence of osteomyelitis with long-term follow-up. 99mTc was shown to be of limited valued when used alone in these patients with peripheral neuropathy. 67Ga, either alone or in combination with 99mTc bone scanning, was of little diagnostic value and gave no additional information that was not available from 111In. The combination of three-phase 99mTc and 111In had the highest diagnostic efficacy (100% sensitivity, 80% specificity, and 91% accuracy), followed closely by 111In alone (100% sensitivity, 70% specificity, and 86% accuracy). We conclude that for adult diabetic patients with clinical suspicion of osteomyelitis but no radiographic findings of that disease, 111In alone is an appropriate nuclear medicine evaluation for ruling out infection if it is negative. However, if an area of 111In white blood cell uptake is present, a "simultaneous" 99mTc is often helpful in providing the anatomic correlation to differentiate osteomyelitis from infection that is limited to soft tissue.