Abstract: According to adverse circumstances and strong blown sand of desert, based on pipeline route, reliability and transportation requirements for long-distance natural gas pipeline in desert area, objective function of minimal total cost within designed life span are established, taking the capital construction investment and annual operation cost into account comprehensively. An optimizing model for long-distance gas pipeline transmission is set up and Mixed and Discrete Optimal Design algorithm (MDOD) is used for the resolve. Such optimal process parameters as operation, pipe material and laying mode of natural gas pipeline in desert region are acquired, which will help to reduce total investment, ensure design quality and increase economic benefit effectively.