This paper deals with a method to evaluate and optimize the design of railway wheels subjected to multiparameter variable fatigue loading. The fatigue loads are statistically evaluated from in-service measurements. Representative realistic loading paths are built from the knowledge of the influence of various factors (such as train speed and track curvature). Using these paths, the method combines finite element computations and the fatigue equivalence method for damage evaluation in the structure. An extension of the Dang Van fatigue criterion in the high-cycle fatigue finite life domain associated with a damage accumulation law is adopted. The probability of failure of the structure is directly obtained from the interference between a local fatigue equivalent stress and fatigue strength distributions (based on the stress-strength interference approach). The result is useful for the optimization during the design stage or the validation of the fatigue strength of structures.