In the frame of a sustainable development, investigations dealing with massive Hydrogen production bymeans of nuclear heating are carried out at CEA. For nuclear safety, thermodynamic efficiency and wasteminimization purposes, the technological solution privileged is the coupling of a gas cooled Very HighTemperature Reactor (VHTR) with a plant producing Hydrogen from an Iodine/Sulfur (I/S) thermochemicalcycle. Each of the aforementioned facilities presents different risks resulting from the operation of a nuclearreactor (VHTR) and from a chemical plant, including Hydrogen, other flammable and/or explosiblesubstances as well as toxic ones. Due to these various risks, the safety approach is an important concern.Therefore, this paper deals with the preliminary CEA investigations on the safety issues devoted to the wholeplant, focusing on the safety questions related to the coupling between the nuclear reactor and the Hydrogenproduction facility. Actually, the H2 production process and the energy distribution network between theplants are currently at a preliminary design stage. A general safety approach is proposed, based on a DefenceIn Depth (DID) principle, permitting to analyze all the system configurations successively in normal,incidental and accidental expected operating conditions. More precisely, the dynamic answer of aninstallation to a perturbation affecting the other one during the previous conditions, as well as, the potentialaggressions of the chemical plant towards the nuclear reactor have to be considered. The methodologypresented in this paper is intended to help the designer to take into account the coupling safety constraintsand to provide some recommendations on the global architecture of both plants, especially on their couplingsystem. As a result, the design of a VHTR combined to a H2 production process will require an iterativeprocess between design and safety requirements.