Cerebral white matter (WM) degradations may represent one of the earliest brain changes in older adults at-risk for cognitive impairment. Such changes have not been comprehensively explored in the brainstem, despite research demonstrating susceptibility of this region to both vascular and Alzheimer’s disease pathology. Therefore, the present study leveraged sensitive multi-shell diffusion tensor imaging (DTI) to characterize brainstem WM microstructure and potential associations with vascular and genetic risk in a sample of cognitive normal (CN) older adults and those with mild cognitive impairment (MCI). Exploratory analyses examined the relationship between antihypertensive medication use, vascular risk, and brainstem WM. Fifty-seven older adults (CN = 47; MCI = 10; mean age = 74.2 years) underwent neuropsychological assessment, whole-brain multi-shell DTI, and apolipoprotein-E (APOE) genotyping. Comprehensive neuropsychological criteria were employed for MCI diagnostics (Jak, Bondi et al., 2009). Arterial stiffness (AS) and Framingham Stroke Risk Profile (FSRP) reflected vascular risk. ANCOVAs revealed no cognitive group differences in brainstem WM integrity (ps > .05). Multiple linear regression demonstrated that higher AS was associated with reduced WM integrity in the inferior cerebellar peduncle (ICP; p = .05), with trend-level associations in the middle cerebellar peduncle [MCP] (p = .07) and left superior cerebellar peduncle (SCP; p = .09). After adjusting for age and FSRP scores, greater AS significantly predicted reduced MCP WM integrity (p = .03). While APOE-e4 status was not associated with brainstem WM (ps > .05), antihypertensive medication use predicted reduced WM integrity across several tracts (ps < .04). Finally, adjusting for age, sex and total number of medications, there was an interaction between antihypertensive medication use and AS such that greater AS predicted reduced fronto-pontine tract integrity in medicated but not unmedicated participants (p = .025). Findings provide preliminary evidence for an association between increased AS and reduced brainstem WM in the context of aging. This relationship appears to be complex, and possibly dependent on medical factors, including use of antihypertensive medications. Future prospective studies are needed to further clarify the nuanced relationship between brainstem WM changes and vascular risk factors in order to better characterize risk for poor outcomes in aging.