Background: Cerebral infarction involving the insula has been associated with decreased survival following stroke. We hypothesized that infarct volume may reduce this association. Methods: The subjects were acute stroke patients who had consented to 2-year follow-up after stroke as part of the Michigan Acute Stroke Care Overview and Treatment Surveillance System registry. One hundred and eleven subjects exhibited areas of acute ischemic infarction on neuroimaging studies, 25 of whom had infarction involving the insula. Cox proportional hazard ratios (HR) were calculated to determine the association between mortality and acute infarction involving the insula, infarct volume, and other factors known to affect survival after stroke. Results: In unadjusted analysis, subjects with insula infarction had a nonsignificant twofold increase in 1-year mortality (HR = 2.1, 95% CI 0.6–7.0; p = 0.25). When adjusted for infarct volume, however, the HR for insula infarction was reduced to the null value (HR = 1.0, 95% CI 0.2–4.1; p = 1.00), indicating that the effect of insula infarction was entirely confounded by infarct volume. Conclusions: Insula infarction was associated with a nonsignificant twofold increase in mortality after stroke; however, this association was completely eliminated after adjusting for infarct volume. Infarct volume thus should be considered in future studies of insula infarction and mortality.