This Safety Guide provides recommendations on safety in the siting, design, construction, commissioning, operation and preparation for the decommissioning of nuclear fuel reprocessing facilities to meet the relevant requirements established in the IAEA Safety Standards Series No. SSR-4, Safety of Nuclear Fuel Cycle Facilities. It provides specific recommendations on the safety of nuclear fuel reprocessing facilities that use the PUREX process to reprocess fuels containing uranium and plutonium. It does not specifically address the reprocessing of thorium from fast breeder reactors or other advanced reactor systems, or the partitioning of radionuclides other than uranium and plutonium. However, the similarity between aqueous processes allows for the application of most of the recommendations provided in this Safety Guide, with suitable adjustments to facilities reprocessing other types of nuclear fuel. This publication is intended for operating organizations and designers of nuclear fuel reprocessing facilities and relevant technical support organizations and regulatory bodies.