Cocaine is a known risk factor for several vascular ischemic events. The underlying mechanisms leading to the complications are not fully understood, although thrombus formation and accelerated atherosclerosis are prominent findings. Evidence of endothelial dysfunction (ED), a key phenomenon in the pathogenesis of atherogenesis, has been demonstrated in cocaine-dependent individuals. Abnormal regional cerebral blood flow (rCBF) is a common finding among chronic cocaine users. The aim of this study was to evaluate whether brain perfusion changes were associated with ED markers in cocaine-dependent individuals. Circulating endothelial cells (CECs), soluble intercellular cell adhesion molecule, and the chemokine regulated on activation normal T cells expressed and secreted were measured in 27 DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition) cocaine-dependents patients. Regional cerebral blood flow was assessed using single-photon emission computed tomography at baseline (after recent cocaine consumption) and after 4 weeks of strict abstinence under standard benzodiazepine or antipsychotic therapy. We used statistical parametric mapping analysis to evaluate the covariates. Endothelial cell damage/activation markers were significantly higher in cocaine-dependent individuals after recent consumption and were reduced after 1-month abstinence (P < 0.05). Global rCBF exhibited no significant difference between baseline and after abstinence. When regional perfusion was analyzed in association with ED covariates, significant differences were observed in bilateral cortical areas, including the limbic lobes. We demonstrated an association between systemic ED markers and rCBF in cocaine-dependent patients. These findings suggest that vascular injury may play a role in the pathogenesis of abnormal rCBF.