Introduction The aim of this study was to compare the resistance to cyclic fatigue of ProTaper Next X2 (PTN X2; size 25, 0.06 taper), Hyflex CM (HCM; size 25, 0.06 taper), OneShape (OS; size 25, 0.06 taper), and ProTaper Universal F2 (PTU F2; size 25, 0.08 taper) nickel-titanium files in an artificial root canal with a double (S-shaped) curvature. Methods A total of 160 new PTN X2, OS, HCM, and PTU F2 files were tested in an artificial stainless steel canal with a double curvature. Forty files from each system were rotated until fracture to calculate the number of cycles to failure. The length of each fractured fragment was recorded. Data were analyzed by using one-way analysis of variance and Tukey post hoc tests. Results The resistance to cyclic fatigue of the PTN X2 and HCM instruments was significantly greater than the OS and PTU F2 instruments in the apical curvature (P <.05). There was no statistical difference in the cyclic fatigue resistance of the PTN X2 and HCM instruments in the apical curvature (P >.05). In addition, there was no statistical difference between the OS and PTU F2 instruments in the apical curvature (P >.05). PTN X2, OS, HCM, and PTU F2 instruments showed similar cyclic fatigue resistance values in the coronal curvature (P >.05). Conclusions This study showed that PTN X2 and HCM instruments exhibit greater resistance to cyclic fatigue than OS and PTU F2 instruments in the apical curvature of an artificial canal with a double curvature.