Copper and phosphorus as impurities and nickel as alloying element were already a long time ago identified to significantly affect radiation embrittlement of reactor pressure vessel materials. As a result, the Cu-content in RPV materials is limited to less than 0.1 wt%, the P-content to less than 0.01 wt% and the Ni-content to less than ~1 wt%. These three elements are explicitly considered in most of the available embrittlement trend curves. Beside Cu, P and Ni, also Mn and Si were also proposed to influence irradiation embrittlement. Indeed, these two elements are found in the irradiation-induced solute clusters examined with atom probe tomography. This paper aims to examine the possible synergy between copper and phosphorus on one hand, and nickel and manganese on the other hand. Therefore, chemically-tailored steels including twelve steels with variable copper/phosphorus contents and nine steels with variable nickel/manganese contents were irradiated at 290 C in the BR2 high flux reactor to various fluence levels ranging between about 1 and 6 1019 n/cm2. The concentrations of the key elements were selected such as to have three distinct levels covering low, medium and high levels. Finally, two steels with all Cu/P/Ni/Mn contents at their minimum and maximum levels were also selected for comparison. Typically, for each steel, small size tensile specimens were irradiated in the BR2 reactor and located in the axial position of the reactor to reach four different neutron fluence levels with three tensile specimens at each position. All tests were performed at room temperature. The results clearly show that, within the composition ranges and experimental conditions considered herein, while copper has a dominant effect, phosphorus contribution is not significant. Moreover, no synergy between these two elements could be evidenced. For the second series of materials with variable nickel and manganese content, the latter does not seem to affect irradiation hardening for all compositions except the high nickel/high manganese steel. However, this last material exhibits an atypical behavior that can be attributed to deformation-induced martensitic transformation. This is supported by transmission electron microscopy examination of undeformed and deformed steels in the unirradiated and irradiated conditions and by experiments on pre-deformed and annealed tensile specimens.