This paper focuses on the microstructural evolution of the M5 alloy under irradiation for fast neutron fluences up to 17.1 × 10²⁵ n/m² (E > 1 MeV) in pressurized water reactors (PWRs). The precipitates and especially the radiation-enhanced particles were studied first with analytical transmission electron microscopy (ATEM) and transmission x-ray diffraction (T-XRD) analyses at the SOLEIL synchrotron facility. Then ATEM was used to study the evolution versus the fast neutron fluence of 〈a〉- and 〈c〉-component loops in M5 alloy and RXA Zy-4. Original T-XRD permitted us to measure the composition and the lattice parameters of the radiation-enhanced precipitation of nanometric needle-like particles. Accurate evolutions of microstructural features such as 〈c〉-component loops, 〈a〉-loops, natives, and radiation-enhanced precipitates have also been determined as a function of irradiation doses up to 20 × 10²⁵ n/m². The precipitate study permitted us to propose an evaluation of the niobium content in the matrix during irradiation. All these results confirm the noteworthy microstructural and microchemical stability of the M5 alloy during irradiation, especially at doses of at least 8 × 10²⁵ n/m². The βNb native particles present in M5 alloy remain fully crystalline after irradiation. After a fluence of 11 × 10²⁵ n/m², native particles reach the “equilibrium” composition of 55 % Nb under irradiation. The irradiation-enhanced precipitation leads to a noticeable decrease in Nb content in the matrix, but no further evolution in size, density, or niobium content seems to occur for these particles after a dose of 8 × 10²⁵ n/m². Finally, the density of 〈c〉-component loops observed in this work for M5 cladding tubes remained moderate relative to that for Zy-4 alloy even for the highest dose of irradiation. We can also underline that the iron content in M5 in Zr1 %NbO_A and Zr1 %NbO_B alloys does not seem to influence either 〈c〉-component loop linear density or needle-like particle size or density in the range of 100 to 650 ppm.