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Objective To analyze the preventive effect of mecobalamin combined with glutathione on neurotoxicity induced by FOLFOX4 chemotherapy. Methods Ninety-four patients receiving FOLFOX4 chemotherapy between January 2012 and December 2013 were randomized into experimental group and control group. Patients in the experimental group were given mecobalamin tablets and glutathione injection during chemotherapy while the patients in control group received glutathione injection only. The status of neurotoxicity was evaluated by the Levi neurotoxicity criteria 1992. Results After six cycles of chemotherapy, the incidence of grade Ⅰ-Ⅱ neurotoxicity in the experimental and control groups were 34.7% (17/49) and 55.6%(25/45), respectively (P=0.042), the incidence of grade Ⅲ neurotoxicity in the experimental and control groups were 2.0%(1/49) and 13.3%(6/45), the difference is also statistically significant (P=0.037). After nine cycles of chemotherapy, significantly less grade Ⅰ-Ⅱ neurotoxicity was observed in the experimental group (44.6%) than that in the control group(70.3%, P=0.019). Incidence of grade Ⅲ neurotoxicity in the experimental group was significantly lower(4.26%) than that in the control group(18.9%, P=0.031). Conclusion Mecobalamin combined with glutathione can significantly reduce the incidence and severity of neurotoxicity induced by FOLFOX4 chemotherapy, therefore, worthy of clinical application. [ABSTRACT FROM AUTHOR]