In positron emission tomography (PET) studies involving organs different from the brain, ignoring the metabolite contribution to the tissue time-activity curves (TAC), as in the standard single-input (SI) models, may compromise the accuracy of the estimated parameters. We employed here double-input (DI) compartmental modeling (CM), previously used for [¹¹C]thymidine, and a novel DI spectral analysis (SA) approach on the tracers 5-[¹⁸F]fluorouracil (5-[¹⁸F]FU) and [¹⁸F]fluorothymidine ([¹⁸F]FLT). CM and SA were performed initially with a SI approach using the parent plasma TAC as an input function. These methods were then employed using a DI approach with the metabolite plasma TAC as an additional input function. Regions of interest (ROIs) corresponding to healthy liver, kidneys and liver metastases for 5-[¹⁸F]FU and to tumor, vertebra and liver for [¹⁸F]FLT were analyzed. For 5-[¹⁸F]FU, the improvement of the fit quality with the DI approaches was remarkable; in CM, the Akaike information criterion (AIC) always selected the DI over the SI model. Volume of distribution estimates obtained with DI CM and DI SA were in excellent agreement, for both parent 5-[¹⁸F]FU (R(2) = 0.91) and metabolite [¹⁸F]FBAL (R(2) = 0.99). For [¹⁸F]FLT, the DI methods provided notable improvements but less substantial than for 5-[¹⁸F]FU due to the lower rate of metabolism of [¹⁸F]FLT. On the basis of the AIC values, agreement between [¹⁸F]FLT K(i) estimated with the SI and DI models was good (R² = 0.75) for the ROIs where the metabolite contribution was negligible, indicating that the additional input did not bias the parent tracer only-related estimates. When the AIC suggested a substantial contribution of the metabolite [¹⁸F]FLT-glucuronide, on the other hand, the change in the parent tracer only-related parameters was significant (R² = 0.33 for K(i)). Our results indicated that improvements of DI over SI approaches can range from moderate to substantial and are more significant for tracers with a high rate of metabolism. Furthermore, they showed that SA is suitable for DI modeling and can be used effectively in the analysis of PET data.