Recently, a new generation of nickel-titanium (NiTi) rotary instruments including the Twisted File (TF; Sybron Dental Specialties, Orange, CA) and ProFile GT Series X (GTX; Denstply, Tulsa Dental Specialties, Tulsa, OK) was introduced to the market. The purpose of this study was to determine if these new NiTi instruments were more resistant to cyclic fatigue compared with traditionally ground NiTi rotary instruments such as EndoSequence (ES; Brasseler, Savannah, GA) and ProFile (PF; Dentsply, Tulsa Dental Specialties). Size #25 TF, ES, and PF and size #20 GTX with .04 and .06 tapers were tested in a simulated canal with 60 degrees angle of curvature and a 3-mm radius. The number of rotations until fracture was recorded for each instrument. Among both .04 and .06 tapered files, #20 GTX files performed significantly better than all other files tested with tip sizes of #25 (p < 0.001); this may be because of the increased flexibility in the #20 files compared with #25 files. TF was significantly more resistant to cyclic fatigue than ES (p < 0.05) but not different from PF (p > 0.05) with the same tip size. The new manufacturing processes appeared to offer greater resistance to cyclic fatigue in a simulated canal model.