To evaluate the impact of different file access angles and root canal curvature's location on the fatigue failure of One Curve (OC) and E3 Azure (EZ) NiTi files using a dynamic model at simulated body temperature. Eighty new instruments with similar tip sizes and taper (#25/0.06) from two NiTi rotary systems, One Curve and E3 Azure, were tested at simulated body temperatures (37°C) using a custom-made dynamic cyclic fatigue device. Instruments were divided into four subgroups according to the location of root canal curvature (a coronal curve 5 mm from the root canal orifice and an apical curve 10 mm from the root canal orifice) and the angle of file access (0° or 30°). Instruments were operated in simulated stainless-steel canals having a 60° curve and a 3 mm radius. A custom-made device produced controlled vertical pecks during file rotation. Time to failure (sec) was registered, and the length of the fragment segments was measured (mm). Data were analysed statistically with One-Way ANOVA and Tukey post hoc tests. The significance level was set at 5%. All separated instruments were examined by scanning electron microscope. One-way ANOVA (p<0.05) found a significant difference among the tested instruments. Post Hoc analysis revealed lower cyclic fatigue resistance when the angle of file access was 30º, and the root canal curvature was located coronally for both files (p<0.0001). Three-way ANOVA showed that the angle of file access was the most influential contributor to cyclic fatigue, followed by the location of file curvature and, finally, the file type (p<0.0001). The fractographic examination revealed a predominantly ductile fracture mode for all tested instruments. The lengths of all fractured segments showed no significant difference (p>0.05), indicating an accurate trajectory during testing. OC files had superior cyclic fatigue resistance than EZ files; coronal curvatures negatively impacted cyclic fatigue resistance compared to apical curvatures, while the angle of file access presented the highest impact on dynamic cyclic fatigue.