Objective: To assess the values of plasma levels of β2-microglobulin (β2-MG) and homocysteine (HCY) for risk rating and prognosis estimation in patients with lower extremity atherosclerotic disease (LEAD). Methods: One hundred and thirty-six patients with confirmed LEAD were enrolled and grouped according to the Fontaine staging as stage I (n=27), stage II (n=39), stage III (n=38) and IV (n=32) group, or according to the values of ankle-brachial index (ABI) as low-risk (0.7≤ABI<0.9, n=36), mid-risk (0.4≤ABI<0.7, n=60) and high-risk (ABI<0.4, n=40) group. In addition, 35 subjects undergoing health maintenance examination during the same period were enrolled as control population for the two hierarchic methods. The plasma levels of β2-MG and HCY were measured and compared among the groups, and the correlation between variables and survival rates were also analyzed. The patients were interviewed every 3 months over a 2-year period. Amputation and death from cardiovascular or cerebrovascular diseases were considered as end-point events, which were also used to determine the prognosis of the patients. Results: The plasma levels of both β2-MG and HCY increased with the progression of the Fontaine stage and with the increase of risk rating as well (both P<0.01). Furthermore, the ABI value was negatively correlated with the plasma levels of β2-MG and HCY (r=–0.867, –0.846). The area under ROC curve of HCY that was used to predict the prognosis of the LEAD patients was 0.831. With a cut-off value at 36.085 (μmol/L), the prediction sensitivity was 86.0%, specificity was 68.6% and Youden index (YI) was 0.546, respectively. COX regression analysis showed the HCY level and ABI value could be used as the independent risk factors to predict the end-point events of LEAD (P=0.018, P=0.001). Conclusion: The plasma levels of β2-MG and HCY increase with the progression of LEAD. HCY is a good index for predicting the occurrence and prognosis of LEAD, but the combined analysis of HCY level and ABI value (risk rating) yields a better judgment of prognosis of LEAD patients.