Objectives <p>Dysregulation of lipid metabolism often occurs in rheumatoid arthritis (RA) patients, and Apolipoprotein E (APOE) is a prominent apolipoprotein involved in regulating lipid metabolism. We aimed to investigate the relationship between <i>APOE</i> genotypes with serum lipids and cardiovascular disease (CVD) risk in RA patients.</p> Methods <p>We recruited 200 RA patients from the Affiliated Hospital of Nanjing University of Chinese Medicine. The high-resolution melting method was used to analyze genomic DNA extracted from the peripheral blood of RA patients. Immunoturbidimetric assay or Colorimetric assay was used to measure clinical laboratory results of RA patients. The differences in clinical laboratory results of <i>APOE</i> genotypes were compared, and the correlation between various indexes and APOE concentration in RA patients with <i>APOE</i> genotypes was analyzed.</p> Results <p>RA patients with ε2/ε3 genotype had lower levels of total cholesterol (TC), low-density lipoprotein (LDL), and apolipoprotein B (APOB) compared with ε3/ε4 genotype patients (<i>p</i> &lt; 0.05). RA patients with ε3/ε4 genotype had significantly higher small dense low-density lipoprotein (sdLDL) and lipoprotein(a) (Lp(a)) compared with ε2/ε3 genotype patients (<i>p</i> &lt; 0.05). Moreover, the APOE concentration of ε2/ε3 genotype was significantly higher compared with ε3/ε4 genotype (<i>p</i> &lt; 0.001), and the APOE concentration of ε2/ε3 genotype was significantly positively correlated with high-density lipoprotein (HDL) and apolipoprotein A (APOA) (<i>p</i> &lt; 0.05), while the APOE concentration of the ε3/ε4 genotype was positively correlated with LDL, APOB, and Lp(a) (<i>p</i> &lt; 0.05).</p> Conclusion <p>This study provides strong evidence that <i>APOE</i> polymorphism is associated with lipoprotein metabolism. The independent risk factors for CVD (sdLDL and Lp(a)), are significantly elevated in ε3/ε4 genotype. APOE concentration is significantly elevated in ε2/ε3 genotype and positively correlated with protective factors for CVD, whereas the opposite is observed in the ε3/ε4 genotype. Therefore, RA patients with ε3/ε4 genotype exhibited dysregulated lipid metabolism, increasing the risk of CVD.<Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> <p><b>Key points</b></p> <p>• <i>In RA patients with ε2/ε3 genotype have lower levels of TC, LDL, and APOB compared with ε3/ε4 genotype</i>.</p> <p>• <i>In RA patients carrying ε3/ε4 genotype have higher levels of sdLDL and Lp(a) compared to carriers of ε2/ε3 genotype</i>.</p> <p>• <i>The role of APOE concentration in RA patients is closely related to APOE genotypes</i>.</p> </entry> </row> </tbody> </tgroup> </Table></p>