Introduction: Sulfredoxin (Srx), which is an endogenous antioxidant substance which could, regulate the signaling pathways of reactive oxygen species. Nuclear factor erythroid 2-related factor 2 (Nrf2) is Cap-N-collar (CNC) transcription factors family member that have essential roles in regulation of antioxidant response. The transcription factor PROX1 is a transcription factor and a key regulatory protein in cancer development. Aim of the study: To analyze levels of tissue expression of Srx, Nrf2, and PROX1 in gastric cancer and adjacent non-neoplastic gastric mucosa to clarify the relationship between their expression levels, clinical, pathological parameters and patients’ outcome. The results might lead to discovering novel targeted therapies to gastric cancers. Material and methods: We included 70 parafn-embedded samples: 50 specimens from gastric carcinomas and 20 specimens from adjacent non-neoplastic gastric mucosa. All samples are stained with Srx, Nrf2, and PROX1 using immunohistochemistry, correlated their expression with clinicopathological and prognostic parameters of patients. Results: High levels of Srx and Nrf2 expression were positively associated with higher cancer grade (p = 0.006, 0.031 respectively), advanced stage (p < 0.001, 0.02 respectively), higher incidence of distant metastases (p = 0.029, 0.03 respectively) and dismal outcome (p < 0.001). High levels of PROX1 expression were associated with lower cancer grade (p = 0.005), absence of lymph nodes metastases (p = 0.023), early stage (p = 0.003), absence of relapse (p = 0.004), and favorable outcome (p < 0.001). Conclusions: Srx and Nrf2 expression increase gastric cancer invasiveness, suggesting their utility as poor prognostic markers, but PROX1 serves as a favorable prognostic marker of gastric cancer patients.