Background: Neurotoxicity is the most common dose-limiting toxicity of oxaliplatin. There is no treatment for cumulative sensory neuropathy. This trial is designed to study the efficacy of Monosialotetrahexosylganglioside (GM1) in GI cancer patients with oxaliplatin-induced peripheral neurotoxicity (OIPN). Methods: In this single center (TJMUCH),double-blind, phase Ⅲ trial, patients were randomized in a 1:1 ratio to receive GM1 or placebo. Patients with OIPN persisting during or after oxaliplatin-based chemotherapy were eligible. The patients who remained on oxaliplatin after enrollment, received concurrent placebo or GM1 x 7 days with each chemotherapy cycle. The patients who stopped taking oxaliplatin, were treated with placebo or GM1 x 14 days every 3 weeks. GM1 was dosed at 60mg daily for every 3-week or 40mg daily for every 2-week schedule. Trial was continued until visual analogy score (VAS) decreased by ≥30% or stayed unchanged after two more treatments beyond completion of oxaliplatin. The primary endpoint was reduction of modified EORTC QLQ-CIPN20(MCIPN20) score by ≥30%. Secondary endpoints were improvement of VAS by ≥30%, CTCAE grade by≥1. Patients who received ≥1 treatment cycle were included in the analysis. Chi-square tests were used for statistical analysis. Results: From May 2015 to Dec 2017, 73 patients were enrolled in GM1 and 72 in placebo arm. 39 (53%) patients in GM1 and 10 (14%) in placebo arm achieve ≥30% reduction in MCIPN20 (RR = 3.85, 95% CI, 2.08-7.11, P < 0.0001). 36 (49%) patients in GM1 and 16 (22%) in placebo arm had ≥30% improvement of VAS (RR = 2.22, 95% CI,1.36-3.623, P = 0.001). The median treatment cycles of GM1 was 2 (range,1-7). Majority of patients in both arms (89% in GM1 and 83% in placebo) continued receiving oxaliplatin on the trial. There were no significant differences in CTCAE and acute neurotoxicity grading between the two arms. There was no ≥G3 GM1 related adverse events. Conclusion: GM1 effectively reduces OIPN in GI cancer patients. The observed clinical benefit is independent of oxaliplatin discontinuation. Trial: NCT02486198 (Drug was afforded by Qilu Pharmaceutical Co., Ltd, China). Clinical trial information: NCT02486198