Film cooling is a common cooling design in aerospace high temperature components, and it is also a typical fatigue risk point of the whole structure. To optimize designs of film cooling holes, an experimental and numerical study was conducted to investigatred fatigue properties of GH4169 alloy film cooling holes with different shapes. Results showed that the fatigue life of the circular shaped hole was obviously lower than those of both the oval shaped hole and the dust-pan shaped hole, and the hole shape exhibited a few influence on the fatigue life of the specimens corresponding to the same skew angle of holes. The specimens of the circular shaped hole failed with only one fracture surface, and the fracture surface was perpendicular to the loading direction. However, the specimens of the oval shaped hole and the dust-pan shaped hole failed with master fracture surface and slave master fracture surface, and the fracture surface was along the hole axis direction. Fatigue crack initiation occurred at the middle region of the circular shaped hole, while fatigue crack initiation occurred at both the entrance and the exit of the oval shaped and the dust-pan shaped hole. The crack initiation zone was flat and smooth, moreover, more dimples were observed on the fracture surface with fatigue crack propagating. Both the skew angle of holes and the shape hole orifice exhibited significant influence on the tress distribution and the peak stress of the hole under quasi-static loading.