Matrix metalloproteinases (MMPs) are proteolytic enzymes which are expressed in atherosclerotic plaques and are thought to participate in the molecular mechanisms mediating atherosclerotic plaque disruption and rupture. Atherosclerosis is an inflammatory disease complicated by the development of rupture-prone atheromas, associated with the development of stenosis or thrombosis. The strictly regulated co-ordinated action of MMPs is primarily regulated at the level of transcription, the promoter cis-regulatory regions of the genes responding to stimuli including macrophage-derived growth factors and cytokines. Functional cis-regulatory variation in the promoters of matrix metalloproteinases leads to low- and high- transcription activity genotypes. To determine whether the MMP3 and MMP9 promoter genotypes predict the extent of atherosclerosis, the association of the MMP genotypes with different types of coronary lesions was investigated in an autopsy series of 300 middle-aged men (aged 35-65 years). In addition, the association with the number of defects in the internal elastic lamina (IEL) of the artery wall was investigated in the major abdominal arteries in an autopsy study of 123 subjects (90 male and 33 female, aged 18-93). Genotyping at these loci was performed by PCR, restriction enzyme digestion and minisequencing, areas of the coronary wall covered with atherosclerotic lesions were measured using computer-assisted morphometry, and the numbers of defects per millimetre in the IEL were measured by image analysis in samples from the arteries. Men with high promoter activity genotypes for MMP3 had, on average, larger calcified lesion areas than those with the low promoter activity genotype, whereas men with high promoter activity genotypes for MMP9 had larger complicated lesion areas. Men with high promoter activity genotypes for both loci had on average more than two times larger areas of complicated lesions compared with those men who had low promoter activity genotypes, but the loci showed no association with acute myocardial infarction. Men with high-activity genotypes for MMP9 had a higher number of gaps per millimetre in the IEL of the right and left renal arteries than did those with the low-activity genotypes. These results suggest that the MMP3 and MMP9 cis-regulatory variants and combinations of genotypes at these loci may contribute to heterogeneity in the presentation of atherosclerosis. This may be mediated via effects on cell fate and the number of different cell types within the vessel wall.