Peripheral artery disease (PAD) is a chronic cardiovascular disease that results in catastrophic consequences, such as lower-extremity amputations, adverse cardiovascular events, and even death. Research has been sparse with regards to tools that can aid physicians with prognostication and risk-stratification of patients with PAD. To identify PAD-specific prognostic biomarkers, in this study, we investigated several proteins involved in angiogenesis with the aim of studying their potential role in predicting major adverse limb effects (MALE) and worsening PAD status (define as drop in ankle-brachial index [ABI] by over 0.15) in patients with PAD. Blood samples were collected from consecutive patients with PAD (n = 250) and without PAD (n = 125) presenting to St Michael's Hospital (Toronto, Canada) who were then prospectively followed for 36 months (3 years). Levels of 17 circulatory proteins involved in angiogenesis proteins were quantified. The primary outcome of this study was MALE (a composite of need for vascular intervention [open or endovascular] or major amputation), whereas the secondary outcome was worsening PAD status (defined as drop in ABI ≥0.15). Multivariable regression analyses were performed to control for potential confounding factors and ascertain the prognostic value of angiogenesis-related proteins in predicting MALE (primary outcome) and worsening PAD status/disease progression (secondary outcome). Survival analyses were conducted to assess freedom from MALE and worsening PAD status. Compared with non-PAD patients, eight angiogenesis-related proteins were differentially expressed in patients with PAD. The primary outcome (MALE) and the secondary outcome (worsening PAD status) were observed in 83 (22%) and 52 (14%) patients, respectively. Of the eight proteins differentially expressed, the most reliable predictor of MALE was hepatocyte growth factor (HGF) (adjusted hazard ratio (aHR) of 0.79 (95% confidence interval [CI], 0.15-0.86). Due to the predictive potential of HGF, we stratified patients into two groups based on their HGF levels: (1) high GHF and (2) low HGF. Relative to patients with high HGF, patients with low HGF had a lower 3-year freedom from MALE (66% vs 88%; P = .001), vascular intervention (68% vs 88%; P = .001), major amputation (93% vs 98%; P = .023), and worsening PAD status (81% vs 91%; P = .006). Based on these data, HGF proteins shows potential in serving as a PAD-specific prognostic biomarker that can help physicians identify PAD patients at risk of MALE.