Deformation and forging operations often introduce microstructural orientation and, therewith, mechanical anisotropy to steel. Flattened manganese sulfide inclusions are held responsible for a great part of fatigue anisotropy. Isotropic-quality (IQ) steel maintains the mechanical isotropy of the material, even after a deformation operation. Isotropic material generally contains little S and, therewith, few manganese sulfides. Further, the IQ steels used in this investigation were Ca treated. The Ca treatment improves the shape stability of the sulfides, even during a hotworking deformation. Two commercial materials were compared for their fatigue response, a standard medium-carbon steel with 0.04 wt pct S and a low-sulfur variant that underwent IQ treatment. The two batches were cross-rolled to plates with a deformation ratio of 4.5, leading to in-plane isotropy. Tension-compression fatigue testing was performed in longitudinal and short transversal directions relative to the rolling plane. The results showed strong anisotropy of the fatigue behavior for the standard material. The performance in the short transverse direction, with the principal stress perpendicular to the flattened inclusions, was inferior. The IQ material with nearly spherical inclusions was almost perfectly isotropic, with only slightly worse fatigue response in the short transverse direction.