Strain controlled low-cycle fatigue tests were conducted on four nickel-base heat-resistant alloys at 900 °C in simulated high-temperature gas-cooled reactor (HTGR) environments and high vacuums of ∼10−1 Pa. The observed behaviors of the materials were different and divided into two groups when tests were made in simulated HTGR helium, while all materials behaved similarly in vacuums. The materials that have relatively high ductility and compatibility with impure helium at test temperature showed considerable resistance to the fatigue damage in impure helium. On the other hand, the alloys qualified with their high creep strength were seen to suffer from the adverse effects of impure helium and the trend of intergranular cracking as well. The results were analyzed in terms of their susceptibility to the environment-enhanced fatigue damage by examining the ratios of the performance in impure helium to in vacuum. The materials that showed rather unsatisfactory resistance were considered to be characterized by their limited ductility partly due to their coarse grain structure and susceptibility to intergranular oxidation. Moderate carburization was commonly noted in all materials, particularly at the cracked portions, indicating that carbon intrusion had occurred during the crack growth stage.