The growing use of creatine as a potential ergogenic aid among active individuals has raised concern regarding its effects on the kidney, particularly among those individuals with compromised renal function. The object of this study is to investigate the effects of oral creatine supplementation in an accepted animal model of renal cystic disease. Han:Sprague-Dawley (SPRD)-cy rats with cystic kidney disease were administered a creatine supplement at a loading dose of 2.0 g/kg of diet for 1 week, followed by 5 weeks during which the dose was one fifth this amount, mimicking typical human consumption on a body-weight basis. Cystic kidney disease progression was assessed by measuring kidney size and fluid content and determining cyst scores. Renal function was assessed by measuring serum urea and creatinine concentrations and creatinine clearance. Creatine supplementation resulted in greater cyst growth and worsened renal function in the Han:SPRD-cy rat, evidenced by greater kidney weights (2.87 +/- 0.08 versus 2.61 +/- 0.09 g/100 g of body weight; P: = 0.0365), renal fluid contents (89.22 +/- 0.41 versus 87.38 +/- 0.48 g/100 g of kidney weight; P: = 0.0057), cyst scores (0.49 +/- 0.02 versus 0.40 +/- 0.03; P: = 0.0167) and serum urea concentrations (23.96 +/- 0.92 versus 20.65 +/- 1.06 mmol/L; P: = 0.0230), and lower creatinine clearances (0.125 +/- 0.098 versus 0.162 +/- 0.011 mL/min/100 g of body weight; P: = 0.0159). These results indicate that creatine supplements may exacerbate disease progression in an animal model of cystic renal disease. Although systematic research of the effects of creatine supplementation in humans with compromised renal function is awaited, it follows that creatine should be used with particular caution in individuals with or at risk for renal disease.