PURPOSE: Studies attributing gains in strength and lean body mass (LBM) to creatine monohydrate (CrM) during resistance exercise (RE) training have not assessed these changes alongside cellular and sub-cellular adaptations. Additionally, CrM-treated groups have seldom been compared with a group receiving a placebo similar in nitrogen and energy. The purpose of this study was to examine the effects of a CrM-containing protein-carbohydrate (PRO-CHO) supplement in comparison to a supplement containing a similar amount of nitrogen and energy on body composition, muscle strength, fiber-specific hypertrophy and contractile protein accrual during RE training. METHODS: In a double-blind, randomized protocol, resistance-trained males were matched for strength and placed into one of three groups: protein (PRO), protein-carbohydrate (PRO-CHO) or the same PRO-CHO supplement (1.5g/kg body wt/day) containing CrM (Cr-PRO-CHO) (0.1g/kg body wt/day). Assessments were completed the week before and after a 10 week structured, supervised RE program; strength (1RM, three exercises), body composition (DEXA) and vastus lateralis muscle biopsies for determination of muscle fiber type (I, IIa, IIx), cross-sectional area (CSA), contractile protein and creatine content. RESULTS: Cr-PRO-CHO provided greater improvements in 1RM strength. At least 40% of the strength improvements could be attributed to hypertrophy of muscle involved in this exercise. Cr-PRO-CHO also resulted in greater increases in LBM, fiber CSA and contractile protein compared to PRO and PRO-CHO. CONCLUSIONS: In RE-trained participants, supplementation with Cr-PRO-CHO provided greater muscle hypertrophy than an equivalent dose of PRO-CHO and this response was apparent at three levels of physiology (LBM, fiber CSA and contractile protein content).