OBJECTIVE: This study assessed the benefit of transmission emission tomography (TET) for classification of skeletal lesions in patients with known malignant disease. SUBJECTS AND METHODS: The TET technology combines acquisition of SPECT and CT data using the same imaging device, thus allowing perfect overlay of anatomic and functional images. We performed TET in 47 patients with tumors who had a total of 104 focal lesions found on bone scintigraphy. Technetium-99m diphosphonate was used as the radiopharmaceutical in all patients. Findings of bone scintigraphy (planar and SPECT), SPECT + CT or radiography, and TET were compared with regard to the precise location and nature (benign vs malignant) of each lesion. Validation was achieved by radiologic follow-up on CT, MRI, or radiography, especially for the extremities, and using biopsy results in five patients. RESULTS: TET could classify 88 (85%) of 104 lesions compared with 37 (36%) of 104 on SPECT. When we counted inconclusive studies as positive for cancer, discrepant findings between SPECT and TET were obtained in 39 lesions. In 38 (97%) of these, TET was correct. Sensitivity for cancer detection was 98% for TET and 94% for SPECT (p = 0.63), and specificity was 81% for TET and 19% for SPECT (p < 0.0001). The highest diagnostic gain was in the spine, thoracic cage, skull, and pelvis. Small osteolytic lesions were missed because of the limited resolution of transmission images. SPECT + CT or radiography and TET were discordant in nine of 104 lesions. TET was false-negative in one lesion and false-positive in another, and SPECT + CT or radiography was false-positive in seven lesions. As a result, sensitivities of TET and SPECT + CT or radiography were nearly the same, but the specificity of TET was significantly higher (p = 0.015). CONCLUSION: TET improves the accuracy of bone scintigraphy by correctly classifying equivocal lesions, especially by identifying benign abnormalities in the axial skeleton and thus increasing the specificity of positive findings.