Tissue inhibitors of metalloproteinases (TIMP1, TIMP2, TIMP3) are naturally occurring inhibitors of matrix metalloproteinases (MMPs). It has been proposed that MMPs have a role in weakening the fibrous cap and subsequent plaque rupture. We hypothesized that TIMP polymorphisms could predispose to premature coronary artery disease. As a first step, we examined the relevant loci using a linkage approach. Sibling pairs recruited for the British Heart Foundation (BHF) Family Heart Study with premature coronary artery disease were examined. Two to three microsatellite markers were examined per TIMP gene. These markers were either intragenic or very close to the locus encoding for the gene. Products were analyzed by capillary gel electrophoresis. Single and multipoint linkage analysis based on the likelihood ratio test was performed using SPLINK and Mapmaker/Sibs software; 417 families were genotyped consisting of 385 sibling pairs, 27 trios, and five sets of four siblings. We were unable to detect linkage of premature coronary artery disease to loci encoding for TIMP1-3. Polymorphisms of the tissue inhibitors of MMP genes do not predispose to premature coronary artery disease in an epidemiologically significant way.