Abstract: 22Cr15Ni3.5CuNbN austenitic heat-resistant steel is a new type of austenitic heat-resistant steel developed for the manufacture of super (super) critical power station boiler pipes at 620 − 650 ℃. The high temperature performance of the material is of great significance to the safe and reliable operation of the unit. In this paper, the stress-strain relationship and fatigue life of 22Cr15Ni3.5CuNbN steel under different strain amplitudes were studied by low-cycle fatigue tests at 650 ℃. The fracture morphology is analyzed to study the fracture mechanism. The results show that 22Cr15Ni3.5CuNbN steel exhibits obvious cyclic hardening behavior at high temperature without obvious stress saturation phenomenon. The cyclic hardening behavior is related to the increase of dislocation density. The fatigue life was predicted based on the plastic strain energy density, and a good prediction effect was obtained. The fatigue fracture can be divided into three regions: crack source region, crack propagation region, and transient rupture region. Multiple crack sources can be observed at the fracture under high strain amplitudes. The formation of multiple crack sources and secondary cracks are important reasons for the decline in fatigue life.