Abstract: The incidence and mortality rate of malignant lymphoma has arisen steadily over the past decade. Vincristine is one of the first-line chemotherapeutic agents used for treating malignant lymphoma, but dose-dependent neurotoxicity can restrict the clinical application of this medicine. This study aims to access the clinical efficacy of glutathione for preventing vincristine-induced neurotoxicity during chemotherapy in lymphoma patients. Methods: One hundred malignant lymphoma patients who received CHOP or R-CHOP regimens including vincristine were randomized into two groups: the glutathione group treated intravenously with glutathione before chemotherapy ( n = 49 ), and the control group ( n = 51 ). The degree of neurotoxicity and the chemotherapeutic efficacy were evaluated every two treatment cycles. The degree of neurotoxicity was accessed by the WHO Toxicity Criteria Scale and the chemotherapeutic effect was evaluated using the Cheson Criteria. Results: The incidence rate of grade I-II and grade III-IV neurotoxicity after chemotherapy was significantly lower in the glutathione group compared to the control group (26.5% vs. 47.1%, P < 0.05; 6.1% vs. 21.6%, P < 0.05 ). In contrast, glutathione pretreatment did not influence clinical efficacy, as overall response after six cycles were 83.7% in the glutathione group and 82.4% in the control group ( P > 0.05 ). Conclusion: The antioxidant glutathione can significantly reduce the occurrence and severity of vincristine-induced neurotoxicity in malignant lymphoma patients without interfering with the clinical efficacy of chemotherapy.