This paper studies the fatigue failure behavior of S135 steel and titanium alloy drillpipe, tries to reveal the mechanism of fatigue fracture, and evaluates the degree of fatigue damage. First, the chemical composition, tensile test, and microstructure analysis of two types of pipes were carried out, and the difference in microstructure affects its macroscopic fatigue performance. Second, the stress vs. fatigue life (S-N) curve equation and fatigue limit of S135 steel and titanium alloy drillpipes in air and mud were obtained through the fatigue test. The equations of the S-N curves in air are and , while in mud, they are and . Scanning electron microscope analysis results show that the S135 steel drillpipe presents brittle fracture, while titanium alloy drillpipe presents mixed fracture of quasi-cleavage and dimple. Finally, a case study of actual horizontal well was carried out to evaluate the fatigue damage of two drillpipes; compared with conventional steel drillpipe, titanium alloy drillpipe can effectively resist fatigue damage in the drilling fluid environment. The fatigue test results and corrosion fatigue mechanism analysis in this paper can provide data and theoretical guidance for the study of drillpipe fatigue life.