Formation of a high density of Mn–Ni–Si nanoscale precipitates in irradiated Cu-free and Cu-bearing reactor pressure vessel steels could lead to severe unexpected embrittlement. Models long ago predicted that these precipitates, which are not treated in current embrittlement prediction models, would emerge only at high fluence. However, the mechanisms and variables that control Mn–Ni–Si precipitate formation, and their detailed characteristics, have not been well understood. High flux irradiations of six steels with systematic variations in Cu and Ni contents were carried out at ∼295 °C to high and very high neutron fluences of ∼1.3 × 10²⁰ and ∼1.1 × 10²¹ n cm⁻². Atom probe tomography shows that significant mole fractions of Mn–Ni–Si-dominated precipitates form in the Cu-bearing steels at ∼1.3 × 10²⁰ n cm⁻², while they are only beginning to develop in Cu-free steels. However, large mole fractions of these precipitates, far in excess of those found in previous studies, are observed at 1.1 × 10²¹ n cm⁻² at all Cu contents. At the highest fluence, the precipitate mole fractions primarily depend on the alloy Ni, rather than Cu, content. The Mn–Ni–Si precipitates lead to very large increases in measured hardness, corresponding to yield strength elevations of up to almost 700 MPa.