In secondary prevention, reduction of the risk of recurrent ischemic stroke might be expected with statins if a correlation can be established between hyperlipidemia and ischemic stroke or some specific ischemic stroke/TIA subtypes. However, such correlation remains controversial, and more particularly with the etiologic stroke/TIA subtypes. Few studies have evaluated the plasma lipid profile in different ischemic stroke subtypes, and notably in lacunar infarctions and cardioembolic strokes. The objectives of this case-control study was to determine (1) which cholesterol fractions is associated with large vessel disease (LVD), small vessel disease (SVD), and cardioembolic disease (CED); (2) whether hypertriglyceridemia is related more to any particular stroke subtype; and (3) whether the lipid profile is different between LVD and SVD which are both responsible for atherothrombotic cerebral ischemia. From a cohort of 485 patients, were selected 240 consecutive cases with ischemic stroke (n = 182) or transient ischemic attack (n = 58) due to a single etiology. The levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), and triglycerides (TG) were measured in 61 patients with LVD, in 65 with SVD, and in 114 with CED, and compared with age- and sex-matched control subjects. Additional analysis was performed to compare the lipid profile between LVD and SVD after adjustment for other risk factors. Compared to controls, the total-C level was significantly higher in patients with SVD (p = 0.005) and LVD (p = 0.018). A significant increase in the LDL-C level (p < 0.004) and a significant decrease in the HDL-C level (p = 0.001) were only observed in the LVD patients. The three stroke subtypes showed higher TG levels than the controls (CED, p = 0.037; SVD, p < 0.001; LVD, p = 0.014). The plasma lipid profile was similar in the SVD and LVD subtypes except for HDL-C, which was significantly lower in LVD than in SVD (p = 0.047). Logistic regression adjusted for confounders showed that decreased HDL-C (p = 0.020), and smoking (p = 0.019) were significant discriminative factors for LVD vs. SVD. In conclusion, this controlled study shows that hypertriglyceridemia is commonly found in patients with ischemic cerebrovascular disease whatever the etiologic subtype, whereas hypercholesterolemia is related more to SVD and LVD. In addition to hypertension and diabetes, hypercholesterolemia may also be involved in the etiology of SVD and differs from LVD by a lower decrease in HDL-C.