OBJECTIVES: We investigated the clinical impact of single-photon emission computed tomography/computed tomography (SPECT/CT) bone scintigraphy combined with 16-slice CT on metastatic workup and treatment planning in a large cancer patient series. METHODS: Between January 2019 and January 2020, a total of 600 cancer patients were prospectively evaluated with whole-body planar bone scan (wbPBS) for staging or restaging purposes. 272/600 had equivocal lesions on wbPBS and 265/272 underwent additionally a targeted SPECT/CT bone scintigraphy on designated regions. Findings were classified as benign (score 1), metastatic (score 2) and inconclusive (score 3). Findings from SPECT/CT bone scintigraphy were compared with the results of wbPBS. RESULTS: A total of 668 lesions were considered as unclear οn wbPBS and were re-evaluated through targeted SPECT/CT bone scintigraphy. Definite diagnostic findings on SPECT/CT bone scintigraphy were obtained in 227/265 (85.7%) patients and in 592/668 (88.6%) lesions vs. 15.4% of wbPBS alone. On per-patient analyses, 38.9% of patients were considered definitely nonmetastatic and 46.8% as definitely metastatic. On per lesion analyses using SPECT/CT bone scintigraphy, corresponding diagnostic rates were 47.5 and 41.2%. Although the addition of SPECT/CT bone scintigraphy significantly reduced the rate of equivocal wbPBS results (83.1%), it failed to provide a conclusive diagnosis in a relatively small proportion of lesions 76/668 (11.4%) in 38 patients. CONCLUSIONS: SPECT/CT bone scintigraphy afforded a significant reduction of the number of patients with equivocal findings who needed further evaluation with other imaging modalities, preventing unnecessary delays in diagnosis and potential changes in disease staging and treatment planning. Moreover, SPECT/CT bone scintigraphy slightly increased diagnostic sensitivity.