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Erosion is one of the important causes of pipeline and equipment damage during hydraulic fracturing. In current research based on erosion simulation, the impact of specific factors on the evaluation of erosion wear has been discussed, while the horizontal comparison of the effects of multiple factors has been ignored. Thus, a method based on an orthogonal experimental design was proposed to study the significant relationship between multiple factors and severity. This can provide the effect ranking of each factor by comparison, and then provide the basis for priority setting of multiple controlling factors and operation steps in the engineering design on pipeline erosion wear resistance. In this case, representative test factors which had impacts on severity (including diameter of pipe, radius of elbow, particle size of proppant, inlet velocity) and test indexes which could measure the severity (including radial velocity, axial velocity, total pressure on pipe wall and maximum erosion rate of pipe wall) were selected. The four factors with a four-level orthogonal experimental design was established and analyzed, and the significant relationship between multiple factors and severity based on the results of mean main effect analysis and variance analysis was studied. The inlet velocity ranked first in all mean main analysis, and had a significant relationship with all four test indexes (the maximum confidence level was 95%), which illustrated that inlet velocity had the largest impact. The elbow radius ranked second in three sets of mean main analysis, and had a significant relationship with three test indexes (maximum confidence level was 95%), which illustrated that the elbow radius had the second largest impact. And the particle size of proppant had the least significance, so that engineering design could give priority to considering the flow velocity and the shape of the elbow to improve the erosion wear resistance of pipelines.