Background: Peripheral vascular disease may manifest as either arterial stenosis or calcification of the arterial wall. Arterial stenosis is characterized by a lowered ankle-brachial-pressure index (ABPI),whereas calcified arteries lead to an increased ABPI. The current study investigates whether inflammatory and oxidative stress markers differ in low versus high ABPI groups suggesting different biochemical processes. Methods: Eighty-seven patients attending the diabetes complications clinic agreed to the study. Participants were divided into a low (<1.07) and a high (>1.23) ABPI tertile groups and compared for traditional and emerging biomarker differences. A clinical history and demographic data were obtained. Emerging biomarkers included C-reactive protein, interleukin-6, 8-hydroxy deoxy-guanosine, D-dimer, reduced glutathione and malondialdehyde. Data was analyzed using a Student T-test with significance set at 0.05. A multivariate normal linear regression model was applied to determine the contributions of traditional and emerging biomarkers to the classification of low and high ABPI. Results: No differences were observed between the two groups for the traditional biomarkers but D-dimer (p < 0.001) and glutathione (p < 0.05) were significantly different between the groups. The best model for predicting ABPI class included the emerging biomarkers C-reactive protein, D-dimer andInterleukin-6 combined with BGL, HbA1c and SBP (p < 0.001) as compared to the best traditional biomarker model of HbA1c, atherogenic index of plasma, low-density lipoprotein and SBP (p < 0.05). Discussion: A decreased inflammatory component with increased oxidative stress is more likely to lead to calcification of the arteries and a higher ABPI, despite normal BGL, HbA1c and cholesterol profile. Our study shows that emerging biomarkers provide a sound basis for differentiating pathophysiological processes associated with low and high ABPI. Traditional biomarkers showed a high accuracy for identification of low ABPI in our model but failed to do better than chance for identification of high ABPI, suggesting different pathophysiological pathways that include oxidative stress and inflammatory components. Clinically, validation of novel and more comprehensive risk factors for PVD sheds light on the etiology of the disease and mechanics of progression toward better preventative care, early detection and targeted drug delivery.