Aicardi–Goutières syndrome is a leukoencephalopathy with calcifications and increased cerebrospinal fluid interferon‐α. The relation between interferon‐α and brain pathology is poorly understood. We report a patient with mutations in the disease‐associated gene SAMHD1. Neuropathology showed an extensive microangiopathy with calcifications consistently associate with blood vessels. In an in vitro model of the microangiopathy, interferon‐α enhanced vascular smooth muscle cell‐derived calcifications. The noninfarcted white matter harbored apoptotic oligodendrocytes and increased numbers of oligodendrocyte progenitors. These findings better define the white matter pathology and provide evidence that interferon‐α plays a direct pathogenetic role in the calcifying angiopathy typical of this disease.