Introduction: Systemic and vascular inflammation are two risk factors for the development of diabetic nephropathy. In diabetic patients, serum systemic and vascular inflammatory factors have positive correlations with albuminuria. The present study was designed to investigate the effects of combined administration of lipoic acid and pyridoxine on the serum concentrations of these factors in patients with diabetic nephropathy. Materials and Methods: The study was a double-blind randomized clinical trial in which 38 patients with diabetic nephropathy (23 females and 15 males) were randomly assigned to either the supplement-taking or the placebo group. The patients in the supplement group received 800 mg lipoic acid and 80 mg pyridoxine daily for 12 weeks, while the placebo group received corresponding placebos. At baseline and the end of week 12, a urine sample and 10 ml blood was collected from each patient after a 12 to 14-hour fast and serum high sensitive C-reactive protein (hs-CRP), soluble intercellular adhesion molecule type 1 (sICAM-1), soluble vascular cell adhesion molecule type 1 (sVCAM-1), sE-selectin, Interleukine-6 (IL-6), glucose, percent of blood hemoglobin A1c and urinary albumin were measured. Results: In the present study, no significant differences were observed between the two groups in mean changes of hs-CRP, IL-6, sICAM-1, sVCAM-1, sE-selectin, glucose, percent of blood hemoglobin A1c. Mean urinary albumin concentration decreased significantly in the supplement-taking group at the end of week 12, compared to the baseline (P<0.05) and the reduction was significant in comparison with the placebo group (P<0.05). Conclusion: The results of the present study indicate that combined administration of lipoic acid and pyridoxine has no effect on serum systemic and vascular inflammatory factors, but it reduces urinary albumin concentration significantly. Therefore, combined administration of lipoic acid and pyridoxine may have an effective role in retarding the progression of diabetic nephropathy with a mechanism different from the effects of these supplements on inflammation.