Resistance training recently was shown to increase myogenic satellite cell (SC) content in trained muscles (Kadi et al., J. Physiol. 558, 2004), which suggests that activation of SC represent an important mechanism during training-induced muscular hypertrophy. It is not known, however, if creatine or protein supplementation combined with resistance training results in amplified gains in SC activation and myonuclei number potentially leading to an enhanced hypertrophic response. PURPOSE: To examine the effect of creatine (CRE) and protein (PRO) supplementation combined with resistance training on skeletal muscle SC content, myonuclei number, mean muscle fiber area (MFA) and maximal muscle strength (MVC). METHODS: Muscle biopsies (VL) were analyzed for fiber area, SC content (NCAM/ D56) and myonuclei number (haematoxylin counterstaining) before, during (wks 4,8) and after 16 wks of resistance training (RT) in young male subjects supplemented by creatine (RT-CRE, n=9), protein (RT-PRO, n=8) or isocaloric placebo (RT-CON, n=8) using a double-blinded study design that included a non-trained control group (CON) (n=7). Maximal isometric quadriceps MVC was obtained by use of static dynamometry (KinCom). RESULTS: SC content increased in all training groups, however gains in RT-CRE (91–109%) were greater than in RT-PRO (45–64%) at wk 8 and RT-CON (30–40%) at wks 4,8 (p<0.05). In contrast, SC content was not elevated relative to baseline in RT-CRE at wk 16. Myonuclei number increased in RT-CRE at wks 4,8,16 (12–16%) and RT-PRO at wk 16 (10%) (p<0.05), while not changing in RT-CON. MFA increased in RT-CRE at wks 4,8,16 (14–17%), in RT-PRO at wk 16(8%), and transiently in RT-CON at wk 4 (13%) (p<0.05). MVC increased to greater levels in RT-CRE than RT-PRO and RT-CON at wk 16 (p<0.05). No changes occurred in CON. CONCLUSION: Creatine supplementation, and to a lesser extent protein supplementation, combined with resistance training appears to augment the training-induced increase in satellite cell content and myonuclei number in human skeletal muscle, resulting in enhanced muscle fiber hypertrophy and amplified muscle strength gains.