 Background: Gastric cancer is the second leading cause of cancer-associated death worldwide, with high incidence in China. The prognosis of advanced gastric cancer is quite poor. Although perioperative chemotherapy may help to prolong survival in cases of advanced disease, radical tumor resection remains the most effective treatment for curable gastric cancer. Nowadays, radical gastrectomy with extended D2 lymphadenectomy has become the standard for treatment of advanced gastric cancer. However, this surgical procedure cannot achieve a radical tumor resection for most cases with advanced disease. Hence, a more extensive D2 plus para-aortic nodal dissection, D4 lymphadenectomy along with gastrectomy has been performed in Japan and other Asian countries. A recent study by Sasako et al. indicated that a prophylactic D4 lymphadenectomy did not improve the prognosis of curable gastric cancer, but increased the blood loss and operation time compared with single D2 procedure. We reviewed our database, which had collected almost 2,000 gastric cancer cases since its establishment in 1994, and found that the D4 surgical procedure actually improved the prognosis of T4 tumor and tumor with lymph node metastasis at the second stations. To further confirm the results from our retrospective analysis, we performed a prospective study with multicenter, open-label, and randomized design in the affiliated hospitals of Sun Yat-sen University. This study would be helpful to improve the prognosis of patients with advanced gastric cancer, and find more efficient management for curable gastric cancer. 