Nodular cast irons are widely adopted in off-highway vehicles, since they allow to obtain components with complex shapes as well as good mechanical properties. However, the fatigue strength of such components is a major issue, which is typically addressed by adopting the strain-life approach, since it considers the local strains at stress concentrators where fatigue cracks are prone to initiate. In the fatigue design of off-highway components, the detrimental effect of casting skin, due to both surface and subsurface features, must be accounted for in all cases where machining is not needed. Moreover, the local strain ratio at stress raisers can be different from the nominal one due to forward plasticity. In this paper, static tensile as well as strain-controlled fatigue tests have been executed on specimens taken from real EN-GJS-450-10 off-highway axles. Static tensile tests have been performed on specimens with machined surfaces, while fatigue tests at a strain ratio equal to −1 have been carried out on specimens with surfaces in both machined and as-cast conditions. In addition, machined specimens have been tested at strain ratios equal to 0.1 and 0.5 to investigate the material sensitivity to the mean strain. Finally, the high-cycle downgrading effect of the casting skin has been evaluated, and experimental data of machined specimens tested at different strain ratios have been summarized by using the Smith–Watson–Topper expression.