Neutron irradiation can promote significant changes in the microstructure and associated mechanical properties of low alloy steels. In particular, irradiation can induce the formation of non-equilibrium phases and segregation, which may lead to a degradation in toughness. In this study, the microstructural changes caused by neutron irradiation have been characterized in A508 Grade (Gr) 4N-type steels (∼3.5% Ni) using a variety of state-of-the-art analytical techniques including 3D-Atom Probe Field-Ion Microscopy and Small Angle Neutron Scattering, along with post-irradiation annealing studies combining Positron Annihilation Lineshape Analysis and hardness measurements. Important differences between conventional and “superclean” A508 Gr 4N steel have been identified in this investigation. The data indicate that Ni is not the controlling factor in the irradiation damage behavior of these materials; rather, the Mn content of the steel is a dominant factor in the irradiation-induced microstructural development of solute-related hardening features.