Defects in natural killer (NK) cell functions are necessary for tumor immune escape, but their underlying regulatory mechanisms in human cancers remain largely unknown. Here we showed, in detailed studies of NK cells from 235 untreated patients with gastric cancer (GC), the NK cell density in GC tissues could predict improved survival of patients. However, NK cells were significantly decreased in number with advanced-stage GC. A multivariate Cox analysis revealed that the intratumoral NK cell density was an independent prognostic factor for overall survival and disease-free survival in the GC patients. Most of the intratumoral NK cells exhibited a normal phenotype and secreted normal levels of cytokines, but the expression of Ki67 was decreased compared with NK cells from nontumoral regions. Moreover, the levels of intratumoral NK cells were negatively correlated with the intratumoral expression of cyclooxygenase-2. Furthermore, we found that PGE2 derived from GC cells suppressed NK cell proliferation and increased apoptosis in vitro. These data reveal that tumor-derived PGE2 is critical for inducing NK cell dysfunction in GC and demonstrate that an extensive infiltration of NK cells predicts a good prognosis in patients with GC. Our findings suggest that immunosuppressive barriers erected by tumors greatly hamper the antitumor activity of human NK cells, thereby favoring tumor outgrowth and progression.