Stroke is one of the most complex diseases with several subtypes, arising from numerous gene-gene and gene-environmental interactions. The aim of our study was to investigate whether the insertion/deletion polymorphism in Angiotensin-converting enzyme gene is associated with ischemic stroke in a South Indian population. One hundred and sixty two patients and one hundred and fifty controls were studied for the presence of ACE gene polymorphism by PCR technique. The stroke patients were subtyped according to TOAST criteria, taking into account all the available data. There were significant differences in the genotypic distribution and allelic frequency between the patients and healthy controls. Furthermore the D allele was significantly associated with intracranial large artery atherosclerosis. However, the association was insignificant with other stroke subtypes. We observed that ACE ID/DD genotypes are associated with an elevated incidence of stroke in a South Indian population from Andhra Pradesh. Moreover, ACE gene polymorphism was found to contribute to the risk of developing intracranial large artery atherosclerosis, which is the most frequent subtype in this region.