Higher levels of cysteinyl cathepsin L were detected in human atherosclerotic lesions than in healthy aortas. However, a link between human coronary heart disease (CHD) and systemic cathepsin L levels remains unknown. A total of 137 volunteers with diagnosed acute and previous myocardial infarction (MI) and stable and unstable angina pectoris in addition to 48 controls were asked to undergo coronary angiography. Serum cathepsin L, high-sensitivity C-reactive protein, fasting glucose, and lipid protein profiles were measured. Serum cathepsin L levels were significantly higher in patients with CHD than in those without CHD (p <0.001). The significance persisted after adjusting for most major confounders. Patients with unstable angina pectoris had higher serum cathepsin L levels than those with stable angina pectoris (p = 0.02). Of patients with acute coronary syndrome, those with acute MI had higher serum cathepsin L levels than those with unstable angina pectoris (p <0.05) and patients with previous MI had the highest levels. Importantly, serum cathepsin L associated positively with number of coronary branch luminal narrowings (R = 0.38, p <0.001), Gensini scores (R = 0.44, p <0.001), high-sensitivity C-reactive protein (R = 0.32, p <0.001), fasting glucose (R = 0.16, p <0.03), and cigarette smokers (R = 0.27, p <0.001), but inversely with high-density lipoprotein (R = −0.23, p = 0.002) and apolipoprotein A1 (R = −0.19, p = 0.01) in all subjects. In conclusion, after adjusting for these confounders, we found that serum cathepsin L correlated positively and independently with Gensini score, suggesting that serum cathepsin L serves as a novel and independent biomarker for CHD.