The purpose of this study was to compare serum growth hormone (GH), testosterone (T), cortisol (C), and whole blood lactate (L) responses to single set (1S) versus multiple set (3S) heavy-resistance exercise protocols. Eight recreationally weight-trained men completed two identical resistance exercise workouts (1S vs. 3S). Blood was obtained preexercise (PRE), immediately postexercise (OP), and 5 min (5P), 15 min (15P), 30 min (30P) and 60 min (60P) postexercise and was analyzed for GH, T, C, and L levels. For 1S and 3S, GH, L, and T significantly increased from PRE to OP and remained significantly elevated to 60P, except for 1S. For GH, T, and L, 3S showed significantly greater increases compared to 1S. For C, 3S and 1S were increased significantly from resting at OP, 5P, and 15P; 3S increased compared to 1S at 5P, 15P and 30P. Higher volumes of total work produce significantly greater increases in circulating anabolic hormones during the recovery phase following exercise.