Cerebral small vessel disease (SVD) accounts for 25-30% of strokes and is a leading cause of cognitive decline and disability. Identification of blood-based biomarkers for SVD may aid in the early identification of high-risk patients and in the understanding of stroke etiologies, which will facilitate development of therapeutic options. In 3,904 men and women from the Atherosclerosis Risk In Communities study, we investigated the association of 245 serum metabolites measured at the baseline examination via untargeted metabolomic profiling with incident stroke subtypes. We focused on strokes with a small vessel pathology. First stroke events occurring between the baseline examination and December 31, 2013 were ascertained by annual telephone interview and hospital surveillance, followed case adjudication by a committee of experienced physicians. Cox proportional hazard models were used to estimate the hazard ratio (HR) for small vessel ischemic strokes (SVIS) per standard deviation of the standardized serum level of each metabolites, adjusting for baseline age, sex, race and field center (model 1); and additionally for diabetes, hypertension, current smoking, body mass index, and estimated glomerular filtration rate (model 2). Over a median follow-up of 24 years, 65 incident SVIS were observed. After correcting for multiple testing, we identified 4 serum metabolites associated with incident SVIS. A deamination product of tryptophan, indole-3-propionate (IPA) remained significantly associated in model 2 (HR [95%CI] = 1.13 [1.07-1.18], P<0.0001). Consistently, this metabolite was also significantly associated with incident hemorrhagic stroke (HR [95%CI] = 1.11 [1.03-1.19], P=0.0074) but no other stroke subtype. Additional analyses of MRI markers of SVD with the identified metabolite will also be presented. In summary, we identified a novel circulating metabolite, IPA, associated with incident ISVS independently of known risk factors. This compound is a potent neuroprotective antioxidant endogenously produced by human microbiota. These results are consistent with a role of oxidative stress in cerebral small vessel pathology.