Layer of protection analysis (LOPA) is a semi-quantitative risk evaluation tool. The methodology is widely used in setting safety integrity level (SIL) targets for safety instrumented systems (SIS). The methodology is often used to evaluate the adequacy of existing protective systems against corporate risk targets. The LOPA method is based on the use of conservative but representative estimates of the failure probability of protective systems. The results of these studies are presented to management for concurrence with the conclusions and for funding of recommendations. Management sometimes asks questions such as: What is the uncertainty in the results? How sensitive are the results to the underlying data and assumptions? How conservative is the LOPA methodology? Should additional independent protection layers be recommended from the LOPA study to compensate for uncertainty in the results? There is no existing method for the analysis of uncertainty in a LOPA study. This article presents a framework to answer management questions related to the LOPA uncertainty. Guidance is presented on methods to incorporate an uncertainty analysis into a LOPA or quantitative risk analysis study. (c) 2012 American Institute of Chemical Engineers Process Saf Prog, 2012