Background. Altered lipid profiles have consistently been linked to cerebrovascular events. Ischemic stroke (IS) was a common comorbid condition established in type 2 diabetes mellitus (T2DM). The apolipoprotein E (ApoE) gene which has a notably critical function in lipoprotein metabolism is believed as one of the potential candidate genes susceptible to IS complications in T2DM. This research aimed to determine the association of apolipoprotein E gene polymorphism with lipid profile and IS risk in T2DM patients. Methods. This case-control study involved a total of 60 diabetic participants divided into two groups with and without IS. ApoE was genotyped using PCR and sequencing analysis. Results. The most predominant genotype observed in 27 participants (45%) was E3/E3. Lower levels of high-density lipoprotein cholesterol (HDL-C) were found in ε2 carriers ( p = 0.003 ; 95% CI −23.35–−4.89) and ε4 carriers ( p = 0.019 ; 95% CI 1.38–14.55) compared to ε3 homozygotes. Total cholesterol (TC), triglyceride, and low-density lipoprotein cholesterol (LDL-C) levels had no association with ApoE gene polymorphism in this study. ApoE gene polymorphism was not related to IS in T2DM ( p = 0.06 ; adjusted OR: 4.71; 95% CI 0.93–23.79). Conclusions. ApoE ε2 and ε4 carriers were associated with lower levels of HDL-C. No association was identified between ApoE gene polymorphism and IS in T2DM patients.