A probabilistic finite element approach to life analysis can be used to assess the structural reliability of a multitude of engineering structures, including medical devices. The framework to this approach, as outlined in this paper, may be useful in cases where quantification of the probability of fracture is of interest. In fatigue life prediction, structural reliability is assessed by combining the stresses developed in a device during component manufacturing with those experienced in the functional or in vivo environment and comparing that total fatigue stress with the fatigue strength of the material as processed in manufacturing the device. Probabilistic finite element analysis for fatigue life prediction is an extension of the deterministic finite element approach, whereby the input control variables are represented with specified probability distributions rather than single values. The input control variables represented by uncertainties require many finite element simulations, which can be created using a design-of-experiments approach. With the probabilistic finite element analysis approach, the probability of fracture is specifically bounded by the statistical distribution of the input control variables. In the present study, a framework is presented for the fatigue reliability analysis of medical devices using the probabilistic finite element approach. This framework is illustrated by a generic design example that includes a response surface model developed to capture fatigue stress distributions in the device with respect to input control variables. Monte Carlo simulations are used to generate the fatigue stress distribution in the device. The resultant fatigue stress distribution is compared with the material’s fatigue strength distribution to estimate the structural reliability against fatigue.