As the largest subcortical commissural fiber, the corpus callosum plays an important role in cerebral functions and has abundant blood supply from bilateral circulation. Isolated corpus callosum infarction (ICCI) may have specific characteristics. The aim of the study is to evaluate the clinical features, etiology, and 6-month prognosis of ICCI. Consecutive patients with acute ICCI treated at the China-Japan Friendship Hospital between June 2012 and June 2016 were retrospectively assessed for clinical and imaging findings. These cases were compared with patients suffering from other isolated supratentorial subcortical infarctions, matched for age, sex, and infarction size (n=60; control group). ICCI etiology and 6-month prognosis were further analyzed. ICCI cases accounted for 2.9% (33/1125) of all acute ischemic strokes and 30 patients were included. Most patients (n=28, 93.3%) presented nonspecific clinical symptoms, and only two (6.7%) with diffuse infarction developed callosal disconnection syndrome (CDS). The splenium was the most frequent site (37.5%). Large artery atherosclerosis (LAA) (n=16, 53.3%) was the most common etiology. Only four (13.3%) patients developed transient ischemic attacks (n=1, 3.3%) or cerebral infarction (n=3, 10%) during the 6-month follow-up. The frequency of good prognosis (modified Rankin score of 1-2 and without cardiovascular events) was higher in patients with ICCI compared with controls (P=0.024). Poor prognosis was associated with multiple cerebrovascular stenosis, diffuse/large infarction, and diabetes (all P<0.05). ICCI is a rare stroke type, frequently involving the splenium; its common etiology is likely LAA. Most patients show nonspecific symptoms, with only a few developing CDS. ICCI generally shows favorable short-term outcome.