Matrix metalloproteinases (MMPs) include most major constituents of the arterial wall as substrates. A common promotor polymorphism (5A/6A) is associated with differences in MMP-3 (stromelysin-1) activity, and associations with certain forms of vascular disease have been shown. This study investigated whether the MMP-3 5A/6A promoter polymorphism contributes to age-related large artery stiffening. MMP-3 5A/6A genotype was determined in 203 (135 male) low cardiovascular risk, unmedicated individuals who were divided prospectively into two groups (30 to 60 years, n=126; > or =61 years, n=77). Noninvasive large artery stiffness was measured as ascending aortic input impedance from brachial blood pressure, carotid tonometry, and Doppler ascending aortic blood flow. In the older group, homozygotes had higher aortic input (P<0.01) and characteristic (P<0.01) impedance, ie, higher stiffness, than heterozygotes after correction for the effects of age, gender, and mean arterial pressure. There was no such difference in the younger group. Gene expression was subsequently investigated in dermal biopsies in randomly selected older men from the same cohort with real-time PCR (n=40). In 5A homozygotes, gene expression was 4-fold higher (P<0.05), and in 6A homozygotes, 2-fold lower (P<0.05) compared with the heterozygotes. Differences in gene expression were associated with corresponding significant changes in MMP-3 protein levels. Concordance between dermal and aortic gene and protein expression was shown in a separate cohort of postmortem aortic samples (n=7). We conclude that MMP-3 genotype may be an important determinant of vascular remodeling and age-related arterial stiffening, with the heterozygote having the optimal balance between matrix accumulation and deposition.