Recent advancements in clinical PET/CT scanners have improved the detectability of small lesions. However, the ideal reconstruction parameters for detecting small lesions have not yet been sufficiently clarified. The purpose of this study was to investigate the detectability of the sub-centimeter spheres using a clinical PET/CT scanner. Methods: We used a Biograph mCT scanner to obtain the data of a NEMA body phantom consisting of 6 small spheres ( inner diameters: 4.0, 5.0, 6.2, 7.9, 10 and 37 mm ) containing 18F solution. The background activity was 2.65 kBq/mL and the sphere-to-background ratio was 8. The PET data obtained for 2 and 120 minutes were reconstructed using on ordered subsets expectation maximization (OSEM) algorithm, OSEM + point-spread-function (PSF) model and OSEM + time-of-flight (TOF) model with the voxel sizes of 2.04 × 2.04 × 2.00 mm (2-mm voxel reconstruction) and 4.07 × 4.07 × 3.99 mm (4-mm voxel reconstruction). A Gaussian filter was not used. The image quality was evaluated by a visual assessment, as well as by a physical assessment of the detectability index and recovery coefficients. Results: According to the visual assessment, the detectability of the spheres improved using TOF and a longer acquisition time. Using the OSEM+TOF model, the smallest visually detected spheres were 5 mm in diameter with 120-minute acquisition, and 6 mm in diameter with 2-minutes acquisition, respectively. According to physical assessment, the detectability of 10-mm or smaller spheres in diameter using the OSEM+TOF image was superior to those on the OSEM image. In addition, the detectability of each hot sphere (DI) and recovery coefficient (RC) with 2-mm voxel reconstruction were superior to those with 4-mm voxel reconstruction. Although OSEM+PSF image showed improvement of background noise, the detectability and the recovery coefficient was not improved for 8 mm or small diameter spheres. Conclusion: The TOF model with 2-mm voxel reconstruction improved the detectability of sub-centimeter hot spheres in clinical PET/CT scanner.