Background and Purpose- Finding adequate control tissue for intracranial aneurysm (IA) pathophysiological studies, including gene expression studies, can be challenging. We compared gene expression profiles of superficial temporal, cortical, and circle of Willis (CoW) arteries and IA in search of the most optimal control tissue for future experiments. Methods- We compared RNA-sequencing data of IA samples and of superficial temporal, cortical, and CoW artery samples using Pearson correlation, Euclidean distance, and principal component analysis. We used the Mann-Whitney U test for comparison of Pearson correlation coefficients and Euclidean distances, to assess which control tissue is most similar to IA in terms of gene expression. Other unrelated tissues were used as negative controls. Results- The cortical and the CoW arteries were more similar to IA in terms of gene expression than the superficial temporal artery. This was based on Pearson correlation (+0.023 [90% CI, 0.017/0.029; P=1.9E-09] for the cortical artery and +0.034 [90% CI, 0.028/0.040; P=6.0E-15] for the CoW artery compared with the superficial temporal artery), Euclidean distance (-25.71 [90% CI, -31.54/-20.02; P=1.9E-11] for the cortical artery and -38.09 [90% CI, -44.08/-32.19; P<2.2E-16] for the CoW artery compared with the superficial temporal artery) and principal component analysis. In all analyses, the unrelated tissues formed separate groups compared with IA and the 3 control arteries. Conclusions- The cortical arteries and the CoW arteries are better controls for gene expression studies on IA than the superficial temporal artery. This probably relates to differences in anatomy of these tissues, such as the presence of an external elastic lamina in the extracranial vasculature and absence in the intracranial vasculature, because IAs, cortical arteries, and CoW arteries are all intracranial while the superficial temporal artery is extracranial. Since CoW arteries can only be obtained postmortem, cortical arteries are preferred over CoW arteries.