OBJECTIVE: Malignant internal carotid artery (ICA) infarction is an entirely different disease entity when compared with middle cerebral artery (MCA) infarction. Because of an increased area of infarction, it is assumed to have a poorer prognosis; however, this has never been adequately investigated. Decompressive craniectomy (DC) for malignant MCA infarction has been shown to improve mortality rates in several randomized controlled trials. Conversely, aggressive surgical decompression for ICA infarction has not been recommended. The authors sought to compare the functional outcomes and survival between patients with ICA infarctions and those with MCA infarctions after DC in the largest series to date to investigate this assumption. METHODS: A multicenter retrospective review of 154 consecutive DCs for large territory cerebral infarctions performed from 2005 to 2020 were analyzed. Patients were divided into ICA and MCA groups depending on the territory of infarction. Variables, including age, sex, medical comorbidities, laterality of the infarction, preoperative neurological status, primary stroke treatment, and the time from stroke onset to DC, were recorded. Univariable and multivariable analyses were performed for the clinical exposures for functional outcomes (modified Rankin Scale [mRS] score) on discharge and at the 1- and 6-month follow-ups, and for mortality, both inpatient and at the 1-year follow-up. A favorable mRS score was defined as 0-2. RESULTS: There were 67 patients (43.5%) and 87 patients (56.5%) in the ICA and MCA groups, respectively. Univariable analysis showed that the ICA group had a comparably favorable mRS (OR 0.15 [95% CI 0.18-1.21], p = 0.077). Inpatient mortality (OR 1.79 [95% CI 0.79-4.03], p = 0.16) and 1-year mortality (OR 2.07 [95% CI 0.98-4.37], p = 0.054) were comparable between the groups. After adjustment, a favorable mRS score at 6 months (OR 0.17 [95% CI 0.018-1.59], p = 0.12), inpatient mortality (OR 1.02 [95% CI 0.29-3.57], p = 0.97), and 1-year mortality (OR 0.94 [95% CI 0.41-2.69], p = 0.88) were similar in both groups. The overall survival, plotted using the Cox proportional hazard regression, did not show a significant difference between the ICA and MCA groups (HR 0.581). CONCLUSIONS: Unlike previous smaller studies, this study found that patients with malignant ICA infarction had a functional outcome and survival that was similar to those with MCA infarction after DC. Therefore, DC can be offered for malignant ICA infarction for life-saving purposes with limited functional recovery.