Existing safety study of building fire is mainly based on the ISO834 temperature-time curve, which is a theoretical curve and not fully reflect the influencing factors of fire such as the distribution of fuel and ventilation of the building. Secondly, the reliability analysis of building fire lacks explicit limit state function, especially when the reliability calculation considers the internal force redistribution of the structure. Direct Monte Carlo simulation has no requirement of explicit limit state function, but it needs huge calculation efforts. To solve these two problems, the response surface method is proposed from the view point of numerical simulation and experiment design. Using the fire modeling software CFAST the actual result of temperature and thickness of smoke layer can be obtained. On this basis, the reliability index can be calculated with the response surface method，which can solve the problem of lacking explicit limit state function by regressing multi-variable function based on the inputs and outputs. Uniform design (UD) method can allocate more parameters without greatly increasing the calculation efforts. Using a case the calculation process is explained with. The results show that this method can quickly obtain the reliability index in the premise of less calculation.