The influence of high-flux helium plasma irradiation on compatibility between liquid lithium and CLF-1 steel, a reduced activation ferritic/martensitic steel, was investigated since CLF-1 shows potential application as substrate material for liquid lithium plasma facing components. After exposure to helium plasma with flux of 5 × 1022 m−2s−1, porous fuzz nanostructures formed on the surface of CLF-1 steel, which size increases with the increasing plasma fluence. The plasma-induced weight loss rate of CLF-1 steel decreased gradually with the increasing He fluence. At 350 °C, the contact angle of lithium droplet on smooth CLF-1 surface was about 60°.After irradiation, the fuzz structure improved the wettability of liquid lithium on the CLF-1 surface due to the increasing surface roughness. After the static corrosion of CLF-1 in liquid lithium at 350 °C for 500 h, the significant chromium depletion, decarbonization and the phase transform from martensite to ferrite were found in both non-irradiated and irradiated samples. The porous fuzz structure significantly aggravates the corrosion behavior. The corrosion occurred preferentially at the grain boundaries for the non-irradiated sample, while the most severe corrosion location was on the top of fuzz protrusion for the irradiated samples.