Aim: To investigate the efficacy of Superoxide Dismutase, Alpha Lipoic Acid, Acetyl LCarnitine, and Vitamin B12 (B12) in one tablet in Diabetic Neuropathy (DN). Patients-methods: In this prospective, double-blind, placebo-controlled study, 85 patients with Diabetes Mellitus Type 2 (DMT2) were randomly assigned, either to receive the combination of four elements (active group, n = 43), or placebo (n = 42) for 12 months. We used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE), measured the vibration perception threshold (BIO), and Cardiovascular Autonomic Reflex Tests (CARTs). Nerve function was assessed by DPN Check [sural nerve conduction velocity (SNCV) and amplitude (SNAP)]. Pain (PS) and quality of life (QL) questionnaires were administered. Results: At follow-up, BIO, MNSIQ, QL, PAIN, and SNCV, SNAP, and B12 levels had significantly improved inactive group (p <0.001, p<0.001, p<0.001, p<0.001, p = 0.027, p = 0.031, and p<0.001 respectively), whereas the inplacebo group MCR (mean circular resultant) and PAIN deteriorated (p<0.001, p <0.001). The changes in MNSIQ, QL, SNCV, BIO, and PAIN differed significantly between groups (p <0.001, p <0.001, p = 0.031, p <0.001, and p <0.001 respectively). Conclusions: The combination of the four elements in one tablet for 12 months in patients with DMT2 improved all indices of peripheral neuropathy, including SNAP and SNCV, pain, and Quality of Life perception, except CARTs and MNSIE.