Objective:To evaluate the effect of all-trans retinoic acid (ATRA) as treatment for chemotherapyinduced peripheral neuropathy in an experimental animal model and in a randomized, doubleblinded, controlled trial in patients with non-small-cell lung cancer (NSCLC). Methods:Forty male Wistar rats were randomized in 5 groups: group A, control; groups B and C, treated with cisplatin; and groups D and E, treated with paclitaxel. ATRA (20 mg/kg PO) was administered for 15 days in groups C and E. We evaluated neuropathy and nerve regenerationrelated morphologic changes in sciatic nerve, the concentration of nerve growth factor (NGF), and retinoic acid receptor (RAR)-␣ and RAR-␤ expression. In addition, 95 patients with NSCLC under chemotherapy treatment were randomized to either ATRA (20 mg/m 2 /d) or placebo. Serum NGF, neurophysiologic tests, and clinical neurotoxicity were assessed. Results:The experimental animals developed neuropathy and axonal degeneration, associated with decreased NGF levels in peripheral nerves. Treatment with ATRA reversed sensorial changes and nerve morphology; this was associated with increased NGF levels and RAR-␤ expression. Patients treated with chemotherapy had clinical neuropathy and axonal loss assessed by neurophysiology, which was related to decreased NGF levels. ATRA reduced axonal degeneration demonstrated by nerve conduction velocity and clinical manifestations of neuropathy grades Ն2.Conclusions: ATRA reduced chemotherapy-induced experimental neuropathy, increased NGF levels, and induced RAR-␤ expression in nerve. In patients, reduction of NGF in serum was associated with the severity of neuropathy; ATRA treatment reduced the electrophysiologic alterations. Classification of evidence:This study provides Class II evidence that ATRA improves nerve conduction in patients with chemotherapy-induced peripheral neuropathy. Neurology ® 2011;77:987-995 GLOSSARY ATRA ϭ all-trans retinoic acid; CI ϭ confidence interval; CIPN ϭ chemotherapy-induced peripheral neuropathy; CP ϭ cisplatin/paclitaxel; DM ϭ diabetes mellitus; NGF ϭ nerve growth factor; NSCLC ϭ non-small-cell lung cancer; OR ϭ odds ratio; QOL ϭ quality of life; qRT-PCR ϭ quantitative reverse transcriptase and real-time PCR; RAR ϭ retinoic acid receptor; RT ϭ radiation therapy.Platinum-based chemotherapy is the first-line therapy for non-small-cell lung cancer (NSCLC) and improves both survival and disease-related symptomatology. 1 However, chemotherapyinduced peripheral neuropathy is common and decreases quality of life (QOL) and may limit chemotherapy doses.2 Cisplatin promotes the formation of free radicals, while paclitaxel blocks axonal transport within peripheral nerves. As many as 38% of patients with NSCLC treated with these drugs develop a disabling sensory neuropathy. 3,4 Retinoids play a critical role in a variety of biological functions, particularly in epithelial and neural differentiation.5 Different types of retinoids possess variable selectivity to retinoidFrom the Laboratorio de Oncología Experimental (Ó ....