Objective: To evaluate the effect of soy protein isolate (SPI) supplementation on some circulating biomarkers of cardiovascular disease (CVD): total homocysteine (tHcy), folate and vitamin B12 in type 2 diabetic patients. Method: Thirty-six type 2 diabetic patients were recruited. They received nutrition counseling and were randomized to SPI group (30 g/day of SPI containing 32 mg of isoflavones for 6 weeks) and control group (no SPI supplement). Anthropometry, blood pressure and biomarkers of CVD were examined at baseline and at the end of 6th week of the study. Results: There were no significant differences in anthropometric parameters, blood pressure and biomarkers of CVD between the 2 groups. At week 6, levels of either tHcy, folate, vitamin B12, or GFR between the two groups did not differ. However, in SPI group, tHcy levels were significantly decreased (P= 0.005) and folate levels were significantly increased from baseline (P = 0.002). Conclusion: This study indicated that supplementation of SPI with isoflavones potentially improves some biomarkers of CVD and may be beneficial on cardiovascular events in type 2 diabetic patients.