Cathepsin L enhances angiogenesis by increasing extracellular matrix degradation and remodelling. This study investigated whether plasma cathepsin L could be used as a biomarker to predict collateral formation in patients with coronary heart disease (CHD). Patients with CHD (n = 218; aged 67 ± 11 years) underwent coronary angiography and were categorized as having either 'poor' or 'rich' collaterals. Plasma cathepsin L, the proangiogenic placenta growth factor (PLGF) and the antiangiogenic factors, cystatin C and endostatin, were measured. Elevated cathepsin L and PLGF levels were independently and significantly associated with enhanced collateral formation in patients with CHD; subgroup analyses also showed a significant correlation in patients with diabetes and acute coronary syndrome. Plasma endostatin and cystatin C levels were not significantly correlated with coronary collateral formation. Plasma cathepsin L and PLGF, acting as important modulators of angiogenesis, could be used as biomarkers to predict coronary collateral formation in patients with CHD.