Sterczala, AJ, DuPont, WH, Comstock, BA, Flanagan, SD, Szivak, TK, Hooper, DR, Kupchak, BR, Lee, EC, Volek, JS, Maresh, CM, and Kraemer, WJ. Physiological effects of nucleotide supplementation on resistance exercise stress in men and women. J Strength Cond Res 30(2): 569–578, 2016—Nucleotide supplementation can reduce postexercise immunosuppression and hypothalamic-pituitary axis (HPA) axis activation in endurance exercise models. Nucleotide supplementation may aid recovery from other exercise modalities, such as heavy resistance exercise. Thus, the purpose of this investigation was to investigate the effects of nucleotide supplementation on the acute cortisol and immune responses to heavy resistance exercise and its effects on recovery. A double-blinded, crossover, mixed methods design with 10 men and 10 women was used. Each performed an acute heavy resistance exercise protocol (AHREP) after a loading period with a nucleotide or placebo supplement. Before and after the AHREP, and at 24, 48, and 72 hours post, blood samples were analyzed for cortisol, myeloperoxidase (MPO), and absolute neutrophil, lymphocyte, and monocyte counts. Creatine kinase (CK) was analyzed before and 24, 48, and 72 hours after the AHREP. Performance measures, including peak back squat isometric force and peak countermovement jump power were also analyzed. Nucleotide supplementation resulted in significant (p ≤ 0.05) decreases in cortisol and MPO immediately after the AHREP, and significantly lower CK values 24 hours later. The AHREP significantly affected leukocyte counts; however, no treatment effects were observed. Greater isometric force was observed immediately after AHREP and at 24 hours and 48 hours with nucleotide supplementation. Nucleotide supplementation seems to attenuate muscle damage, HPA axis and immune system activation, and performance decrements after heavy resistance exercise.