Background and Purpose— Noninvasive imaging identifying a predictive biomarker of the bleeding risk of unruptured intracranial aneurysms (UIAs) is needed. We investigated a potential biomarker of UIA instability, myeloperoxidase, in human aneurysm tissue. Methods — Human brain aneurysms were harvested after clipping and were histologically and biochemically evaluated for the presence of myeloperoxidase. Of the tissue collected, 3 were from ruptured aneurysms and 20 were from UIAs. For each UIA, its 5-year aneurysm rupture risk was determined using the Population, Hypertension, Age, Size of Aneurysm, Earlier Subarachnoid Hemorrhage From Another Aneurysm and Site of Aneurysm (PHASES) model. Results — All ruptured aneurysms were myeloperoxidase positive. Of the UIAs, half were myeloperoxidase positive. The median 5-year aneurysm rupture risk was higher for myeloperoxidase-positive UIA (2.28%) than myeloperoxidase-negative UIA (0.69%), and the distributions were statistically different ( P <0.005, Wilcoxon–Mann–Whitney test). The likelihood for myeloperoxidase-positive UIA was significantly associated ( P =0.031) with aneurysm rupture risk (odds ratio, 4.79; 95% confidence limits, 1.15–19.96). Conclusions — Myeloperoxidase is associated with PHASES estimated risk of aneurysm rupture and may potentially be used as an imaging biomarker of aneurysm instability.