Background: Different models that include clinical variables and blood markers have been investigated to predict acute ischemic stroke treatment course and recovery. Aim: The aim of the study was to investigate associations between lipid levels, lifestyle factors, hemostatic (F5, F2, SERPINE1, F13A1, and FGB), and atherogenic (APOA5 and ACE) gene variants and acute ischemic stroke (AIS) severity. Materials and methods This study included 250 patients with AIS in which F5, F2, SERPINE1, F13A1, FGB, APOA5, and ACE genotypes were determined. Total cholesterol (TC), high-density cholesterol, low-density cholesterol, and triglycerides concentrations were measured within 24 h of the AIS onset. Examination of the neurological deficit was done using National Institutes of Health Stroke Scale/Score (NIHSS). Results: APOA5 genotype [TC + CC] was more frequent (P = 0.026) in patients with the NIHSS score ≥ 21. Univariate regression analysis has shown that triglycerides (OR 0.55, 95% CI 0.34–0.91; P = 0.019), obesity (0.28, 95% CI 0.10–0.73; P = 0.010), age (OR 1.08, 95% CI 1.04–1.13; P < 0.001), and APOA5 genotype (TC + CC) (OR 2.40, 95% CI 1.10–5.25; P = 0.034) are significantly associated with a severe stroke. When all variables were included in model age (OR 1.06, 95% CI 1.01–1.11; P = 0.018), obesity (OR 0.25, 95% CI 0.08–0.77; P = 0.016) and APOA5 genotype (TC + CC) (OR 3.26, 95% CI 1.29–8.23; P = 0.012) remained significant for the risk of severe AIS. Conclusion: APOA5 genotype (TC + CC), age, and obesity could be used as prognostic risk factors for a very severe stroke (NIHSS ≥ 21).