OBJECTIVES To assess the impact of scan- and patient-related factors on the error and the minimum detectable difference in iodine concentration among different generations of single-source (SS) fast kV-switching and dual-source (DS) dual-energy CT (DECT). METHODS Lesions having eight different iodine concentrations (0.2-4 mgI/mL) were emulated in a 3D-printed phantom of medium and large size. Each combination of concentration and size was scanned in dual-energy mode on four different SS and DS DECTs. Radiation doses were 7 and 10 mGy (medium size) and 10, 13, and 16 mGy (large size). Iodine maps were reconstructed with filtered back projection (FBP) and vendor-specific iterative reconstruction algorithms (IRs). Absolute error of iodine quantification (E) was measured. Multivariate regression models determined the influence of CT scanner, iodine concentration, phantom size, radiation dose, and reconstruction algorithm on E. The minimum detectable difference in iodine concentration (IC) under the same imaging conditions (intra-conditional) and among different imaging conditions (inter-conditional) was calculated. RESULTS The error was significantly lower in current than in previous DECT generations (p < 0.001). For all CT scanner conditions, the error was significantly higher with increasing phantom size and decreasing radiation dose (p < 0.001). Iodine concentration only significantly affected the error for SS DECT (p < 0.001). IC depended on patient- and scan-related factors and ranged from 0.4 to 1.5 mgI/mL. CONCLUSIONS Patient- and scan-related factors have a significant impact on the error and minimum detectable difference in iodine concentration within and among SS fast kV-switching and DS DECT. KEY POINTS • Patient- and scan-related factors have a significant impact on the error and minimum detectable difference in dual-energy CT-based iodine quantification. • Third-generation DECTs outperformed second-generation scanners for both single-source and dual-source dual-energy CT. • The minimum intra- and inter-conditional detectable difference in iodine concentration ranged from 0.4 to 1.5 mg iodine/mL.