This report documents the validation of ORIGEN-S computer code predictions of decay heat using experimental benchmarks involving irradiated nuclear fuels. The experiments include the measurements of decay heat for (1) pulse fission irradiations for many fissionable materials in spent fuel for cooling times of interest to severe accident analyses (< 105 s), and for (2) full-length fuel assemblies over longer cooling times of importance to spent fuel storage and transportation. The fuel assembly measurements evaluated in this study include all previously reported measurements performed in the United States at the General Electric Morris Operations facility and at Hanford Engine Maintenance Assembly and Disassembly facility in Nevada. Recent fuel assembly decay heat measurements carried out at the Swedish Central Interim Storage Facility for Spent Fuel, CLAB, are also included. The purpose of this report is to evaluate the computational bias and uncertainty associated with decay heat predictions when using the ORIGEN-S code and cross-section libraries generated employing modules and nuclear data libraries of the SCALE 5 code system. This validation study includes a broader range of assembly designs, fuel enrichments, cooling times, and higher burnup values than has been reported previously. The results will be used to develop technical guidance and recommended margins for uncertainty in decay heat predicted with ORIGEN-S.