The neural precursor cell expressed, developmentally down-regulated 4-like (Nedd4L) gene encodes an ubiquitin ligase that targets the epithelial sodium channel for degradation. Recent studies have demonstrated that Nedd4L plays a role in the progression of various cancers. However, the clinical implications of Nedd4L expression status in gastric cancer have remained unclear. We examined the Nedd4L expression in 82 gastric cancer patients by immunohistochemistry. The correlation between Nedd4L expression and clinicopathological factors, including prognosis, was evaluated. Cancerous Nedd4L expression was detectable in 36 of the 82 tumors (43.9%). Tumors with negative Nedd4L expression had greater extent of lymph node metastasis, lymphatic invasion, and venous invasion, and were at a worse stage than the tumors with positive Nedd4L expression. Additionally, the patients with negative Nedd4L expression had poor clinical outcomes. Furthermore, multivariate analysis indicated that Nedd4L expression was an independent prognostic factor for gastric cancer patients. Our results suggest for the first time that negative Nedd4L expression is strongly related to the invasion and metastasis of gastric cancer. Therefore, Nedd4L expression can be used as an independent prognostic marker of gastric cancer.