We report the allele frequencies of the apolipoprotein B (Apo B) signal peptide polymorphism in patients with myocardial infarction and compare them with controls. The first sample consists of 197 myocardial infarction patients and 168 controls from Belfast (UK). The second sample consists of 167 myocardial infarction patients and 205 controls from Strasbourg (France), and the third consists of 71 patients and 146 controls from Haute-Garonne (Toulouse, France). No significant differences were observed in the frequency distribution of genotypes among cases and controls or between populations. However, there were more rare homozygotes in the Belfast cases. Significant associations were observed between the Apo B signal peptide polymorphism and mean levels of total cholesterol, low density lipoprotein cholesterol, Apo B and lipoprotein particles containing Apo (a) [Lp(a)] in the Strasbourg control population. Individuals homozygous for the rare allele had higher levels of these lipid parameters. In Belfast, although not statistically significant, the Apo B signal peptide polymorphism had a similar effect on Apo-B-related parameters as seen in Strasbourg. No significant associations were observed in the Haute-Garonne population where the risk of myocardial infarction is three times lower than in Belfast. In all three populations, the average Lp(a) levels were consistently different among Apo B signal peptide genotypes. These data implicate the Apo B signal peptide in determining some of the risks of myocardial infarction in these populations. Regardless of the exact mechanism, the Apo B signal peptide is an important candidate locus for the study of potentially atherogenic lipid variants.