To analyze the consequences of the introduction of advanced fuels at high burn-up in Nuclear Power Plants (NPP), the French Institute de Radioprotection et de Sûreté Nucléaire (IRSN) has initiated a research program focused on the study of PWR fuel behavior in Loss-Of-Coolant Accident (LOCA) conditions. A first step of this program, comprising analytical and experimental parts, has been to identify the main physical phenomena, linked with thermal mechanical behavior of irradiated rods in bundle geometry, that need to be taken into account in reactor safety analyses. This paper summarizes an analysis of sensitivity calculations performed with the CATHARE2 “Best-Estimate” code, used in France in the frame of realistic methodology to evaluate safety margins. The objective of these calculations is to identify parameters, among those affecting phenomena in LOCA conditions, that lead to significant uncertainty in global code response. This is the case of the fuel relocation phenomena whose impact is highly dependent on parameters such as, in the example of Large Break LOCA transient, cladding radial and axial deformations, burst criterion, balloon filling rate, thermal hydraulics in ballooned regions. A lack of knowledge of these parameters for irradiated UO2 and particularly MOX fuel may lead to reduced safety margins. This study provides some elements that may help identify future research needs to complement the present experimental database, reduce uncertainties and develop more realistic calculation models, which may better fit the thermo-mechanical behavior of advanced irradiated fuels.