Matrix metalloproteinases (MMPs) are plausible candidates for prediction of unstable coronary syndromes. We hypothesised that the MMP-3 polymorphism (– 1171, 5A/6A) would relate to coronary plaque characteristics and unstable clinical presentation.Forty patients with de novo presentation of coronary artery disease (CAD) were classified into unstable coronary syndrome (n=19) or stable angina pectoris (n=21). On coronary intravascular ultrasound, patients with unstable disease had a greater plaque burden, more positive (outward) coronary remodelling, and all but one were MMP-3 6A allele carriers (p=0.027 compared with stable). The relationship between the 6A allele and unstable presentation was substantiated in a validation cohort of 161 CAD patients (58 stable and 103 unstable) and in the total population of 201 CAD patients (79 stable and 122 unstable, p=0.007), and was independent of conventional risk factors. Furthermore, 6A allele carriers had a higher plasma MMP-3 concentration (15.8±12.5 versus 11.7±7.2 ng/mL, p=0.01), maximum coronary stenosis on angiography (89±15% versus 80±23%, p=0.02), plaque area (12.0±5.2 versus 7.5±3.6 mm 2 , p=0.03), percentage plaque burden (82±7 versus 71±13%, p=0.003), and remodelling ratio (1.03±0.23 versus 0.83±0.12, p=0.003).The MMP-3 6A allele promotes positive coronary remodelling, greater plaque burden, and increased susceptibility to unstable coronary syndromes in humans.