Background: The effects of protein supplementation on muscle thickness, strength and fatigue seem largely dependent on its composition. The current study compared the effects of soluble milk protein, micellar casein, and a placebo on strength and fatigue during and after a resistance training program. Methods: Sixty-eight physically active men participated in this randomized controlled trial and underwent 10 weeks of lower-body resistance training. Participants were randomly assigned to the Placebo (PLA), Soluble Milk Protein (SMP, with fast digestion rate) or Micellar Casein (MC, with slow digestion rate) group. During the 10-week training period, participants were instructed to take 30 g of the placebo or protein twice a day, or three times on training days. Tests were performed on quadriceps muscles at inclusion (PRE), after 4 weeks (MID) and after 10 weeks (POST) of training. They included muscle endurance (maximum number of repetitions during leg extensions using 70% of the individual maximal load), fatigue (decrease in muscle power after the endurance test), strength, power and muscle thickness. Results: Muscle fatigue was significantly lower (P < 0.05) in the SMP group at MID and POST (-326.8 +/- 114.1 W and -296.6 +/- 130.1 W, respectively) as compared with PLA (-439.2 +/- 153.9 W and -479.2 +/- 138.1 W, respectively) and MC (-415.1 +/- 165.1 W and -413.7 +/- 139.4 W, respectively). Increases in maximal muscle power, strength, endurance and thickness were not statistically different between groups. Conclusions: The present study demonstrated that protein composition has a large influence on muscular performance after prolonged resistance training. More specifically, as compared with placebo or micellar casein, soluble milk protein (fast digestible) appeared to significantly reduce muscle fatigue induced by intense resistance exercise.