Background Stroke is a common complication of infective endocarditis (IE). Our aim was to describe the prevalence and prognostic impact of stroke in a national prospective cohort of IE. Methods Consecutive inclusion at 46 Spanish hospitals between 2008 and 2021. Results Out of 5667 IE cases, 1125 had acute stroke (19.8%): 811 ischemic strokes (618 cardioembolic strokes, 193 cardioembolic strokes with hemorrhagic transformation, 4 transient ischemic attacks, 3 lacunar infarctions), 125 intracranial hemorrhages, and 29 other neurological complications (cerebral abscesses, encephalitis, meningitis, seizures). Compared to patients without stroke, those with stroke had a similar mean age (69 years) but were more frequently female (68.2% vs. 63.7%, p=0.04) and had a higher incidence of intracardiac complications (35% vs 30%, p=0.01), surgical indication (69.9% vs 65.9%, p=0.001), in-hospital mortality (40.9% vs. 22.0%, p<0.001), and one-year mortality (46.2% vs 27.9%, p<0.001). The following variables were independently associated with stroke: mitral location (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.34-1.8, p<0.001), vascular phenomenon (OR 2.9, 95% CI 2.4-3.6, p=0.0001), acute renal failure (OR 1.2, 95% CI 1.0-1.4, p=0.021), septic shock (OR 1.3, CI 1.1-1.6, p=0.007), sepsis (OR 1.3, CI 1.1-1.6, p=0.005), surgery indicated but not performed (OR 1.4, 95% CI 1.2-1.7, p<0.001), community-acquired IE (OR 1.2, 95% CI 1-1.4, p=0.017), and peripheral embolization (OR 1.6, CI 1.4-1.9, p <0.001). Stroke was an independent predictor of in-hospital (OR 2.1, 95% CI: 1.78-2.51, p<0.001) and one-year mortality (hazard ratio 1.9, 95% CI 1.6-2.5). Conclusions: One fifth of patients with IE have concomitant stroke. Stroke is associated with mortality.