PROJECT SUMMARY/ABSTRACT Stroke is a major cause of disability and mortality, particularly in low-income individuals and people living with HIV (PLWH). It is associated with a variety of substances, including amphetamines, opiates, cannabis, alcohol, tobacco, and especially cocaine. However, most stroke studies do not account for drug use outside of alcohol or tobacco, and substance use is not included in stroke risk calculators. Our preliminary data suggest that cocaine use may influence mechanisms of stroke. If true, the consideration of cocaine use in stroke risk calculators could greatly improve risk assessment in PLWH who use drugs. We propose a new study to assess whether cocaine and polydrug use, in combination with inflammation, are significantly associated with stroke and mechanisms of stroke. The study will be one of very few to recruit participants from both safety net HIV clinics and community-based settings. It will provide much needed information regarding factors that influence conditions preceding stroke in PLWH who use drugs.