Although numerous fatigue crack growth (FCG) tests have been conducted, the conclusions drawn regarding the mixed-mode FCG rate are inconsistent and even contradictory. A reasonable conjecture is that crack driving force and crack closure effects may play a crucial role in causing this situation. In this paper, the 16MND5 steel, commonly used reactor pressure vessel (RPV) steel, was employed to investigate the mixed-mode I&II FCG behaviors through the compact-tension-shear (CTS) experiments. The influence of crack driving force and crack closure effect was analyzed and discussed. The results show that the crack propagation path tends to maximize the tangential stress component at the crack tip, and the effect of ΔKII can be negligible once the Paris region is reached. Moreover, when considering the crack closure corrected ΔKI, named ΔKI eff, all the FCG rate data under different loading conditions can be collapsed into a narrower band of distribution. The premise for arriving at this result is to use the stress intensity factors solution that are applicable to specimens with real slanted propagating cracks, rather than applying equivalent methods based on single-edge straight crack assumptions. Finally, the fatigue fractography further confirms that the FCG mechanism during the Paris region all follow a similar quasi-mode I behavior.