The apolipoprotein E (APOE) polymorphisms are associated with cardiovascular (CV) disease, but its interaction with type 2 diabetes mellitus (T2DM) long-term incidence is unknown. We investigated the association between APOE genotype and long-term (i) CV events and (ii) T2DM incidence in a Southern European primary prevention cohort.We assessed individual APOE genotypes in a total of 436 patients followed at a lipid clinic, with a 15-year median follow-up time. We collected data on major CV events (CV death, myocardial infarction, and stroke) and T2DM development.No differences were found regarding major CV event incidence among the different APOE genotypes. However, after excluding 39 patients with a prior history of T2DM, APOE2 carriers displayed a higher incidence of T2DM during follow-up (42.2%) than APOE3 (27.1%) and APOE4 (28.7%) carriers. The age-, sex-, triglycerides-, and statin usage-adjusted OR for T2DM incidence in APOE2 carriers was 1.8 (95%CI 1.1-2.9, =0.03), compared with wild-type APOE3. To address the role of statins as a confounder, we analyzed T2DM incidence in statin-treated patients. Statin-treated APOE2 carriers also had a higher T2DM incidence (57.9%), in comparison with APOE3 homozygotes (31.6%) and APOE4 carriers (32.5%). After adjustment for confounding, APOE2 carriers on statins displayed a similar twofold increase in T2DM risk compared to APOE3 homozygotes (OR 2.1, 95%CI 1.1-4.0, =0.03).Our findings suggest a twofold increase in T2DM incidence in APOE2 carriers. This may prompt for a specific glucose dysmetabolism follow-up that might be tailored on the APOE genotype.