To discuss the correlation between homocysteine (Hcy) level and acute cerebral infarction (ACI) combining with white matter ischemic lesion (WMIL) under different disease causes. Methods: A total of 280 patients with ACI combined with WMIL verified by CT and MRI were recruited to this study. Patients were divided into the atherosclerosis thrombotic cerebral infarction only group (AT group), WMIL only group (WMIL group), (AT+WMIL) group, and (SAO+WMIL) group, with 70 patients per group. The level of Hcy was measured for comparisons among groups. Results: The Hcy level of the (AT+WMIL) group and (SAO +WMIL) group was higher than that of the WMIL group (P<0.05, P<0.05). Logistic regression analysis indicated that age and TG are statistically significant factors in ACI patients with WMIL (P<0.05); meanwhile, Hcy showed more statistical significance in these patients (P<0.01). Conclusion: Elevated Hcy level is closely related to ACI with WMIL, but it has no correlation with the etiology of ACI with WMIL.