PURPOSE: To examine the effects of different types of whey protein supplementation and moderate-volume resistance training on lean mass (LM), fat mass (FM), bench press strength (BPMAX) and endurance (BPREPS), leg press strength (LPMAX) and endurance (LPREPS), and thigh muscle cross-sectional area (mCSA) in trained and untrained men. METHODS: Sixty-three healthy men (mean ± SD age: 21.0 ± 2 yrs; height: 178.8 ± 6.8 cm; weight: 77.9 ± 12.8 kg; body fat: 16.8 ± 6.1%) volunteered for testing before and after an 8-week resistance training intervention. BPMAX, BPREPS, LPMAX and LPREPS were determined using a standard one-repetition maximum (1-RM) protocol and repetitions performed to failure on a standard Olympic bench and 45° hip sled, respectively. mCSA at mid-thigh was assessed using a peripheral quantitative computed tomography scanner. Participants were randomly assigned to either a bio-enhanced whey protein (BWP: 20g polyethylene glycosylated whey protein concentrate, 7g leucine, and 200mg proteases; n = 20), standard whey protein (SWP: 20g whey protein concentrate; n = 22) or placebo (PLA: 27g maltodextrin; n = 21) group. The treatment groups were further dichotomized into trained and untrained. All groups consumed a chocolate-flavored shake (BWP, SWP, or PLA) 30 minutes before and immediately after each training session and lifted 3 times per week at 80% of their BPMAX or LPMAX for 8 weeks. RESULTS: Seven separate three-way repeated measures analysis of variance models (time [pre vs. post] × treatment [BWP vs. SWP vs. PLA] × training status [trained vs. untrained]) resulted in no three-way interactions (p>0.05) and no two-way interactions for time × treatment (p>0.05) or treatment × training status (p>0.05) for any variable. However, there were time × training status interactions for BPMAX (p = 0.008) and BPREPS (p = 0.003), but no other significant interactions for any other variable (p>0.05). Post hoc analyses indicated that BPMAX and BPREPS increased (p<0.001) from pre- to post-training in both the trained and untrained. Furthermore, the trained group performed more reps than the untrained group at pre- and post-training (p = 0.001 and p = 0.023, respectively). There were main effects for time for LM (p<0.001), LPMAX (p<0.001), LPREPS (p<0.001), and mCSA (p<0.001). Finally, there were also main effects for training status for LM (p = 0.005), LPMAX (p = 014), and mCSA (p = 0.025). CONCLUSIONS: The resistance training improved all parameters, except FM, for all supplement groups, including the placebo. Furthermore, the initial training status did not influence the outcome, since both trained and untrained men improved from pre- to post-training, despite the trained group having more lean mass, higher BPMAX, LPMAX and mCSA at pre- and post-training than the untrained men. The untrained men performed better at post-training only for BPREPS. PRACTICAL APPLICATIONS: Practitioners and strength coaches can use moderate-volume training to increase lean mass, strength, muscular endurance, and hypertrophy for athletes or the general population, regardless of their initial training status or protein supplementation. ACKNOWLEGMENTS: This study was funded by a grant from the General Nutrition Corporation, Pittsburgh, PA.