Fatigue tests of nickel-based single-crystal superalloys with inclined film cooling holes (FCHs) at 1000°C were conducted to investigate the effects of crystal orientation and to quantify the fatigue performance of the high-temperature structures. Fractographic analysis and computations of stress concentrations revealed competitive failure mechanisms between mode I crack nucleation and fatigue crack growth in crystallographic plastic slip systems, whereas crack nucleation around inclined FCHs can be characterized by the known fatigue criteria derived for smooth specimens. A life prediction model based on the crystal slip mechanism and the theory of critical distance was introduced to predict the fatigue life of FCH structures and provided reasonable accuracy for different FCH specimens.