This study was designed to investigate the effects of combined administration of lipoic acid and pyridoxine on albuminuria, oxidative stress, blood pressure, serum advanced glycation end-products, nitric oxide (NO), and endothelin-1 in patients with diabetic nephropathy. Thirty-four patients were randomly assigned to either a supplement group or a placebo group. The patients in the supplement group received 800 mg lipoic acid and 80 mg pyridoxine daily for 12 weeks, whereas the placebo group received corresponding placebos. Urinary albumin, serum malondialdehyde (MDA), and systolic blood pressure decreased significantly in the supplement group compared to the placebo group (p < 0.05). Serum NO increased in the supplement group compared to the placebo group (p < 0.05). Serum pentosidine and carboxymethyl lysine decreased significantly in the supplement group at the end of week 12 compared to baseline (p < 0.05). No statistically significant differences were observed between the two groups in mean changes of serum endothelin-1, glucose, and diastolic blood pressure. The present study indicates that combined administration of lipoic acid and pyridoxine improves albuminuria in patients with diabetic nephropathy by reducing oxidative stress, advanced glycation end-products, and systolic blood pressure. The reduction in microalbuminuria may be of benefit in retarding the progression of diabetic nephropathy.