Abstract: Objective:To explore the mechanism and reversing effect of tetramethylpyrazine (TMPZ) and cyclosporine A (CsA) on multidrug resistance (MDR) in treating malignant lymphoma (ML). Methods:A total of120 ML patients with pathologically confirmed relapse and drug resistance were randomly divided into four groups: (A) TMPZ + CsA + chemo-therapy, (B) CsA + chemotherapy, (C) TMPZ + chemotherapy and (D) chemotherapy alone. Flow cytometry was used to an -alyze the P-gp expression, and sub-group analysis was conducted based on the P-gp expression.Results: Complete data for 108 of the 120 patients were available for evaluation. The progression-free survival (PFS) of the patients was higher in group (A) than in group (D) (P=0.0346). There were no statistically significant differences in the comparison between the other two groups (P>0.05). There was a higher overall response rate (ORR) in the reversal-agent groups (A, B and C) than in the control group (D) (P<0.05). The subgroup analysis has shown that P-gp (+) was seen in 76patients. The PFS of the patients with P-gp (+) was higher in group (A) and (C) than in group (D), with statistical differences among the groups (P<0.05). The PFS of patients with P-gp (+) was higher in group (B) than in group (D), nevertheless, there were no statistical differences between the two groups (P>0.05). The ORR was higher in the patients with P-gp (+ ) in the reversal agent groups (A, B and C) than those in the control group (D), with statistical differences among the groups ( P<0.05). There was a manifest advantage in the ORR in group (A) compared with that in groups (B) and (C), (P<0.05). P-gp (-) was seen in 32 patients. Concerning PFS and ORR of the patients, there were no statistically significant differences in comparison among the groups ( P>0.05). No obvious adverse side effects were seen with TMPZ and CsA treatments. Conclusion:TMPZ and CsA can, to a certain degree, reverse MDR in relapsed or refractory ML and is closely correlated with the P-gp expression. There is an improved curative effect in the combined therapy of the two drugs.