In the present study, we tested the hypothesis whether creatine, a metabolite of arginine metabolism, shares the pharmacological activities of arginine reducing collagen accumulation in the diabetic kidney. Ten db/db mice were given, for 3 months, a solution containing a daily dosage of creatine of 50 mg/kg body weight. Eleven db/db mice served as controls. At the end of the 3-month study period, the mean N-carboxymethyllysine concentration in the untreated group was significantly higher than in the treated group (0.163 ± 0.18 versus 0.096 ± 0.017 nmol/μmol hydroxyproline, p < 0.001). Collagen accumulation was also significantly higher in the untreated than in the treated group (2.21 ± 0.24 versus 1.68 ± 0.22 μmol hydroxyproline/100 mg kidney weight, p < 0.001). We conclude that creatine led to a significant reduction in collagen type IV accumulation resembling arginine or aminoguanidine action. We do suggest that the guanidino group common to both compounds is able to block reactive carb