Purpose The use of SPECT/CT in bone scans has been widespread in recent years, but there are no specific guidelines concerning the optimal acquisition protocol. Two strategies have been proposed: targeted SPECT/CT for equivocal lesions detected on planar images or systematic whole-body SPECT/CT. Our aim was to compare the diagnostic accuracy of the two approaches. Methods 212 consecutive patients with a history of cancer were referred for bone scans to detect bone metastases. Two experienced readers randomly evaluated for each patient either planar images with one-field SPECT/CT targeted on equivocal focal uptakes (targeted SPECT/CT) or a whole-body (two-field) SPECT/CT acquisition from the base of the skull to the proximal femurs (whole-body SPECT/CT). The exams were categorized as “nonmetastatic,” “equivocal,” or “metastatic” on both protocols. The presence or absence of any extra-axial skeletal lesions was also assessed. The sensitivity and specificity of both strategies were measured using the results of subsequent imaging follow-up as the reference standard. Results Whole-body SPECT/CT had a significantly higher sensitivity than targeted SPECT/CT to detect bone metastases (p = 0.0297) and to detect extra-axial metastases (p = 0.0266). There was no significant difference in specificity among the two approaches. Conclusion Whole-body SPECT/CT is the optimal modality of choice for metastatic workup, including detection of extra-axial lesions, with improved sensitivity and similar specificity compared to targeted SPECT/CT.