Abstract The published data remain inconsistent on association between apolipoprotein E (APOE) gene variations and plasma levels of C-reactive protein (CRP), mainly because of low statistical power of previous studies. To clarify this question, we analyzed data from large population sample of randomly selected individuals from seven Czech towns (2,886 males and 3,344 females, the HAPIEE [Health, Alcohol, and Psychosocial factors In Eastern Europe] study). In both males and females, the lowest levels of plasma hsCRP were observed in the carriers of the APOE ε4ε4 and ε4ε3 genotypes. The median (interquartile range, IQR) concentration of hsCRP in carriers of the most common APOE ε3ε3 genotype (two-thirds of participants) was 1.13 mg/l (IQR, 0.56–2.33) in men and 1.23 mg/l (IQR, 0.61–2.65) in women, compared with 0.72 mg/l (IQR, 0.61–0.86) in male and 0.72 mg/l (IQR, 0.61–0.85) in female carriers of APOE ε4ε3/ε4ε4 genotypes; the differences were statistically significant (p < 0.001). The association between APOE and CRP was not materially affected by adjustment for age, sex, history of cardiovascular disease, or cardiovascular risk factors. This study, the largest to date, provides robust evidence of an association between plasma hsCRP and the APOE genotype, an association not explained by history of cardiovascular disease nor its risk factors.