We aimed at estimating additive genetic heritability, household component effect and the influence of common alleles of the apolipoprotein E gene (APOE) on serum high-sensitivity C-reactive protein (hs-CRP) concentrations and the subsequent changes over 5 years. A sub-sample of 320 nuclear families was randomly selected from the Stanislas Family Study. Serum hs-CRP concentration was measured by immunonephelometry at entrance and after 5 years. APOE alleles were determined by restriction fragment length polymorphism. After adjustment for covariates, the number of the epsilon4 allele was negatively associated with serum concentration of hs-CRP in the whole sample, at entrance and 5 years later, without significant interaction with sex by generation groups (P=0.003 and P=0.0003, respectively). However, no significant association was found between epsilon4 allele and 5-year changes in hs-CRP concentration. Using a variance component analysis, no significant genetic influence was shown in family aggregation of both hs-CRP measurements and 5-year changes; the household common component was between 6.5 and 12.8%. In addition, after adjustment for APOE gene polymorphisms, degrees of resemblance were almost unchanged. In the Stanislas Family Study, epsilon4 allele of the APOE gene was associated with lower hs-CRP concentration, but not with 5-year changes. However, variance component analysis did not evidence a significant polygenic effect.