Abstract: The reliability-based design method can be used to analyze quantitatively the uncertainty factors at different ultimate limit states (e.g. load and resistance) in the actual failure mode of pipelines, so as to guarantee the safety and reliability of pipelines. Based on life-cycle cost comparison, the pipe material, construction, operation, maintenance and failure consequences can be balanced so as to realize the optimal pipeline economy while the pipeline is kept safe. For a certain natural gas pipeline with the diameter of 273 mm, the wall thickness was designed by using the reliability-based design method for the first time. The critical wall thickness corresponding to the target reliability was calculated by the uncertainty parameters (e.g. pipe material, construction and operational maintenance) which were acquired by means of survey and study. According to the standard wall thickness in design code, the life-cycle cost was quantitatively calculated and analyzed for the schemes with wall thickness of 5.2 mm, 5.6 mm, 6.4 mm and 7.1 mm, respectively. It is indicated that the scheme with the wall thickness of 5.2 mm is the lowest in construction and operation costs while its potential loss cost is much higher than the other schemes due to its high failure probability. The 6.4 mm scheme is the lowest in life-cycle cost and its total cost in 30 years is 0.51% lower than that of 5.2 mm scheme. When safe reliability and economic applicability are taken into consideration comprehensively, it is recommended to adopt the scheme with wall thickness of 6.4 mm.