Objective: To evaluate the efficacy and safety of trigonella foenum-graecum L. total saponins (TFGs) in combination with sulfonylureas (SU) in the treatment of patients with type 2 diabetes mellitus (T2DM) not well controlled by SU alone. Methods: Sixty-nine T2DM patients whose blood glucose levels were not well controlled by oral sulfonylureas hypoglycemic drug were randomly assigned to the treated group (46 cases) and the control group (23 cases), and were given TFGs or placebo three times per day, 6 pills each time for 12 weeks, respectively. Meanwhile, the patients continued taking their original hypoglycemic drugs. The following indexes, including effects on traditional Chinese medicine (TCM) symptoms, fast blood glucose (FBG), 2-h post-prandial blood glucose (2h PBG), glycosylated hemoglobin (HbA1c), clinical symptomatic quantitative scores (CSQS), body mass index (BMI), as well as hepatic and renal functions, were observed and compared before and after treatment. Results: The efficacy on TCM symptoms was obviously better in the treated group than that in the control group (P<0.01), and there were statistically remarkable decreases in aspect of FBG, 2h PBG, HbAlc and CSQS in the treated group as compared to those in the control group (P<0.05 or P<0.01), while no significant difference was found in BMI, hepatic and renal functions between the two groups (P>0.05). Conclusion: The combined therapy of TFGs with sulfonylureas hypoglycemic drug could lower the blood glucose level and ameliorate clinical symptoms in the treatment of T2DM, and the therapy was relatively safe.