Background: In the past, there were not a lot of studies on how A-kinase anchor protein 5 (AKAP5) involving in the pathogenesis and prognosis of non-mucin producing stomach adenocarcinoma (NMSA). Therefore, we studied the relationship between AKAP5 and the prognosis of NMSA and its possible mechanisms using publicly available data from The Cancer Genome Atlas (TCGA) Methods: RNA high-throughput sequencing and clinicopathologic data of NMSA were downloaded from the TCGA. Clinical pathologic features associated with AKAP5 expression were analyzed using the chi-square and Fisher exact tests. The relationship between the overall survival (OS) and AKAP5 expression was analyzed by the Kaplan-Meier method and the Cox regression analysis. GSEA analysis was performed using the TCGA dataset. Results: Our results indicated that the AKAP5 expression was increased in NMSA (all tumor vs. adjacent mucosa). Also, histologic grade, clinical stage, N classification, and survival status were significantly correlated with AKAP5 expression. Kaplan-Meier curves showed that low AKAP5 expression was associated with a poor OS among the NMSA patients (P=5.003e-05), and in the clinical stage III and IV (P=4.646e-05), TNM stage T3 (P=0.016), T4 (P=0.001), N2 (P=0.012), N3 (P=0.003), MO (P=3.911e-05), and histological grade G3 (P=1.658e-04) subgroups. Cox regression analysis showed that reduced AKAP5 expression in NMSA is associated with age (HR =1.03, P=0.007), stage (HR =1.84 for stage I, II vs. stage III, IV, P=0.002) and M classification (HR =1.8 for MO vs. M1, P=0.010). Gene sets related to cholesterol homeostasis, glycolysis, estrogen response late, adipogenesis, estrogen response early, notch signaling, and peroxisome were differentially enriched with the low AKAP5 expression phenotype. Conclusions: Low expression of AKAP5 may be a potential molecular marker for predicting poor prognosis of NMSA. Besides, cholesterol homeostasis, glycolysis, estrogen response, adipogenesis, notch signaling, and peroxisome may be the key pathways regulated by AKAP5 in NMSA. It also suggested that AKAP5 might potentially have biological functions in the development of stomach adenocarcinoma.