A current concept for the development of diabetic long-term complications is the involvement of oxidative stress, as, e.g., lipid peroxidation, in the diabetic state. Data published recently show also oxidative damage to DNA, which might be one factor for accelerated aging and diabetic microangiopathy. In our study we tested the hypothesis that L-arginine can reduce lipid peroxidation in patients with diabetes. We performed a blind placebo controlled study with crossing over two treatment periods for 3 months. Thirty patients with diabetes mellitus were randomly assigned to treatment group A (first treatment then placebo) and B (first placebo then treatment). Treatment consisted of two daily dosages of 1 g L-arginine free base. Lipid peroxidation as reflected by malondialdehyde was evaluated in urine using a standard HPLC assay. After 3 months of treatment there was a significant reduction in malondialdehyde levels in group A (p < .0032), whereas there was no difference compared to the baseline values after three months of placebo treatment in group B (p < .97). After crossing over, there was a significant reduction in malondialdehyde levels in group B (p < .0002). Group A showed a significant increase in malondialdehyde levels (p < .0063) returning to baseline values. L-Arginine treatment was able to reduce the lipid peroxidation product malondialdehyde. This provides evidence that treatment with L-arginine may counteract lipid peroxidation and thus reduce microangiopathic long-term complications in diabetes mellitus.