Human reliability assessment (HRA) is an aspect of risk analysis concerned with identifying, analyzing, and quantifying the causes, contributions, and occurrence of human failures. Applications of existing HRA methods are often domain-specific, and difficult to implement even for experts. Also, due to the lack of empirical data, managing uncertainty is important, if not essential. In view of such limitations, we propose a new and comprehensive HRA methodology acronymed “PRELUDE” (Performance shaping factor-based human REliability assessment using vaLUation-baseD systEms). It is a quantitative and qualitative HRA methodology, applied to railway operations. The qualitative part characterizes a safety critical situation using performance shaping factors (PSFs). The PSFs are identified from domain specific human factors and PSF-based studies. The quantitative proposition is a framework of a graphical model (Valuation-based System) and belief functions theory. Appropriate representation and handling of all types of uncertainties, and combination of conflicting expert opinions is considered in this framework. To aid in the choice of appropriate combination method, combined expert data are discussed and compared using quantitative metrics. PRELUDE allows quantifying a human failure event given an operational context. Sensitivity analysis is used to establish a priority ranking among the PSFs. Finally, application on a railway accident scenario describes usage and applicability of our proposition.