In heavy section cast iron components, anomalous microstructures can be formed especially at the core, because of low cooling rate, with a consequent decrease in mechanical properties. The matrix microstructure, the presence of surface defects, such as inclusions and porosities, and the size and morphology of graphite nodules are critical issues to ensure the adequate performance of the component in fatigue applications. Proper design of heavy section ductile iron castings requires a database of information about microstructures and mechanical properties that nowadays is missing or is very poor. In this paper, we presented the mechanical characterization of ductile irons with solidification times up to 20 h, carried out to identify the metallurgical and the process parameters that most affect the improvement in fatigue strength. An innovative production line was designed, aimed at reproducing on a small-scale sample the characteristics of heavy walled components. A standard ferritic ductile cast iron compared to a ferritic cast iron with high silicon content and a fully pearlitic ductile cast iron were studied by tensile, Brinell hardness and rotating bending fatigue tests. Optical microscope analysis and scanning electron microscope observations of the most significant fracture surfaces were also performed. It was concluded that the ferritic cast iron is more suitable for the production of large thickness castings undergoing fatigue loads, because the decrease in ductility and its effect on other properties is less pronounced.