Nanocrystalline and ultrafine-grained (UFG) metals produced by severe plastic deformation exhibit often microstructures with elongated grains, which result in orientation dependent mechanical properties. This anisotropy is especially pronounced for the resistance against quasi-static and cyclic crack growth. In order to gain more knowledge about the consequences of anisotropic microstructures in the case of cyclic loading, fatigue crack growth (FCG) experiments were performed on UFG iron processed by high pressure torsion, with a mean grain size of 500 × 400 × 150 nm3. Samples with four different orientations were prepared and tested with two mean stresses to account for crack closure effects. The FCG rate varies by one order of magnitude between cracks propagating parallel to elongated grains and cracks advancing perpendicular to it. This larger difference is discussed in the light of intrinsic and extrinsic toughening mechanisms. It is concluded that crack closure contributions are reduced in UFG Fe, however, geometric shielding due to more frequently occurring crack branching leads to a significantly higher FCG resistance for cracks perpendicular to the grain elongation. Furthermore, it is observed that grain refinement leads to a transition from transgranular to intergranular fracture. However, it can be shown that this intergranular crack growth of UFG iron under cyclic loading is not the result of grain boundary embrittlement, but occurs due to a blunting and re-sharpening process along the grain boundaries.