The radioiodine isotope pair 124I/131I is used in a theranostic approach for patient-specific treatment of differentiated thyroid cancer. Lesion detectability is notably higher for 124I PET (positron emission tomography) than for 131I gamma camera imaging but can be limited for small and low uptake lesions. The recently introduced silicon-photomultiplier-based (SiPM-based) PET/CT (computed tomography) systems outperform previous-generation systems in detector sensitivity, coincidence time resolution, and spatial resolution. Hence, SiPM-based PET/CT shows an improved detectability, particularly for small lesions. In this study, we compare the size-dependant minimum detectable 124I activity (MDA) between the SiPM-based Biograph Vision and the previous-generation Biograph mCT PET/CT systems and we attempt to predict the response to 131I radioiodine therapy of lesions additionally identified on the SiPM-based system. A tumour phantom mimicking challenging conditions (derived from published patient data) was used; i.e., 6 small spheres (diameter of 3.7–9.7 mm), 9 low activity concentrations (0.25–25 kBq/mL), and a very low signal-to-background ratio (20:1). List-mode emission data (single-bed position) were divided into frames of 4, 8, 16, and 30 min. Images were reconstructed with ordinary Poisson ordered-subsets expectation maximization (OSEM), additional time-of-flight (OSEM-TOF) or TOF and point spread function modelling (OSEM-TOF+PSF). The signal-to-noise ratio and the MDA were determined. Absorbed dose estimations were performed to assess possible treatment response to high-activity 131I radioiodine therapy. The signal-to-noise ratio and the MDA were improved from the mCT to the Vision, from OSEM to OSEM-TOF and from OSEM-TOF to OSEM-TOF+PSF reconstructed images, and from shorter to longer emission times. The overall mean MDA ratio of the Vision to the mCT was 0.52 ± 0.18. The absorbed dose estimations indicate that lesions ≥ 6.5 mm with expected response to radioiodine therapy would be detectable on both systems at 4-min emission time. Additional smaller lesions of therapeutic relevance could be detected when using a SiPM-based PET system at clinically reasonable emission times. This study demonstrates that additional lesions with predicted response to 131I radioiodine therapy can be detected. Further clinical evaluation is warranted to evaluate if negative 124I PET scans on a SiPM-based system can be sufficient to preclude patients from blind radioiodine therapy.