This study evaluated the effects of high-dose of short-term creatine supplementation (5g.kg^-1.day^-1 to 1 week) and long-term creatine supplementation (1g.kg^-1. day^-1 to 4-8 weeks) on kidney and liver structure and function of sedentary and exercised Wistar rats (Exercise sessions consisted of swimming at 80% of maximal work load supported during 5 days per week with daily sessions of 60 minutes throughout the duration of the supplementation). Seventy- two animals (245 ± 5g) were divided into four groups (n = 18): control diet Sedentary (SED), Creatine diet Sedentary (CRE), control diet Exercised (EXE), and Creatine diet Exercised (EXECRE). Histological and blood biochemical studies were performed after one, four, and eight weeks of creatine supplementation and exercise (n = 6). No differences were found when comparing SED, EXE and EXECRE groups for kidney and liver structure and function at one, four and eight weeks. However, the CRE group showed higher levels of creatinine (1.1 ± 0.2 vs. 0.4 ± 0.1 mg.dl^-1; p < 0.05), and urea (37 ± 3 vs. 19 ± 1 mg.dl^-1; p < 0.05) when compared with all others groups at four and eight weeks. At eight weeks, the CRE group presented increased levels of ALT (41 ± 7 vs. 23 ± 7 U.L^-1; p < 0.05), AST (89 ± 6 vs. 62 ± 5 U.L^-1; p < 0.05), GGT (8.0 ± 0.9 vs. 3.9 ± 1.0 U.L^-1; p < 0.05), and AP (125 ± 10 vs. 69 ± 9 U.L^-1; p < 0.05) also when compared with all others groups. Moreover, the CRE group demonstrated some structural alterations indicating renal and hepatic damage at four and eight weeks, respectively. These results suggest that long-term creatine supplementation (up to 4-8 weeks) may adversely affect kidney and liver structure and function of sedentary but not of exercised rats.

• Creatine supplementation is an established ergogenic aid in sports and is now claimed to have therapeutical applications in a variety of diseases.

• Although acknowledged, this nutritional supplement is rarely monitored precisely about their possible side effects.

• Previous studies indicated that short-term creatine supplementation associate with the physical exercise may be safe, but the effect of long-term creatine supplementation is still unknown.

• There is a need for further research to elucidate the controversial points refers to renal and hepatic function after creatine supplementation.

• The results of the current study indicate that supraphysiological long-term creatine supplementation (up to 4-8 weeks) may adversely affect kidney and liver structure and function of sedentary but not of exercised rats.