Antegrade cerebral perfusion (ACP) is standard treatment for complex aortic pathology and includes both unilateral (u-ACP) and bilateral (b-ACP) techniques. Focusing on proximal acute aortic dissection, we investigated the clinical effect of u-ACP versus b-ACP. From January 2005 to May 2013, 157 consecutive patients presented with acute type A aortic dissection. Antegrade cerebral perfusion was used in 153 patients (97.4%). Ninety patients (58.8%) received u-ACP, and 63 (41.2%) received b-ACP. No retrograde cerebral perfusion was used. The target systemic hypothermia temperature during ACP was 22° to 24°C. The mean ACP, cardiopulmonary bypass, and cardiac ischemia times were 34.6 ± 18.0, 125.6 ± 48.0, and 92.6 ± 34.1 minutes, respectively. The p values from logistic regression models indicated that in both groups combined, the ACP, cardiopulmonary bypass, and cardiac ischemia times predicted hospital mortality (p = 0.035, p = 0.0033, and p = 0.035, respectively) but not stroke. The operative mortality was 13.3% (n = 12) with u-ACP and 12.7% (n = 8) with b-ACP (p = 0.91). Of the survivors, 13 of 88 u-ACP patients (14.8%) and 8 of 62 b-ACP patients (12.9%) had a postoperative stroke (p = 0.75). A circulatory arrest time of >30 minutes was associated with stroke (p = 0.031). Temporary neurologic dysfunction was present in 10 u-ACP (11.4%) and 5 b-ACP (8.2%) patients (p = 0.53). Postoperative renal failure occurred in 10 u-ACP (11.4%) and 10 b-ACP patients (16.1%) (p = 0.40). Antegrade stent delivery in the descending thoracic aorta did not affect the ACP, cardiac ischemia, circulatory arrest, or cardiopulmonary bypass times. As one of the largest single-center studies of the efficacy of u-ACP and b-ACP in patients with type A aortic dissection, operative mortality, stroke, temporary neurologic dysfunction, and renal failure rates were similar in both. In this intrinsically complex disease, survival is the most important outcome; u-ACP may provide cardiac surgeons with valuable technical simplicity during challenging procedures, and b-ACP may be justified for circulatory arrest times of more than 30 minutes.