Acute ischemic stroke (AIS) is a major complication in left ventricular assist device (LVAD) population. A better understanding of clinical risk factors associated with AIS may help mitigate risk of stroke. We reviewed prospectively collected data of 477 LVAD patients from a tertiary center from October 1, 2004 to December 31, 2016. Supplemental data abstraction was performed on patients with AIS. Fifty-seven (12%) developed 61 AIS. Of 61, 17 (28%) AIS occurred perioperatively. The median time from implant to perioperative AIS was 5 days (interquartile range: 3-9). Pump thrombosis accounted for 19 (31%) of 61 AIS, and 7 (37%) presented initially with AIS before the pump thrombosis. The median lactate dehydrogenase (LDH) at the time of AIS in the pump thrombosis group (806) was higher than LDH at 1 month (437, P = 0.27) at 3 months (334, P = 0.01), and 6 months (286, P = 0.001) before AIS. Thirty-three (54%) AIS occurred while receiving inadequate antithrombotic therapy. Acute infections were common (31, 51%) in AIS and 12 (20%) were associated with acute bloodstream infection. All AIS were explained by a combination of four clinical risk factors. All LVAD-associated AIS occurred perioperatively or in conjunction with pump thrombosis, subtherapeutic anticoagulation, and bloodstream infection. The common underlying thread is occurrence of a prothrombotic state. The results of this study underscore the potential consequences of disruption of delicate hemostatic balance in patients with LVAD.