Background: ADP-ribosylation factor 6 (ARF6) is a small GTPase in the RAS superfamily, which regulates membrane trafficking, remodeling and tumor progression. Preclinical study shows that TP53 and KRAS cooperatively activate the ARF6-AMAP1 pathway which serves as a link by which pancreatic driver mutations promote tumor invasion, PD-L1 dynamics and immune evasion properties in pancreatic ductal adenocarcinoma (PDAC). The clinical impact of ARF6 on cancer progression and prognosis remains unclear. Methods: A total of 2,948 PDAC samples were analyzed using next-generation sequencing of RNA (whole transcriptome, NovaSeq) and DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ). QuantiSeq (Finotello 2019, Genome Medicine) was used to quantify immune cell infiltration. Overall survival (OS) was obtained from insurance claims, and Kaplan-Meier estimates were calculated for molecularly defined cohorts. Significance was determined as p values adjusted for multiple correction (q) of <.05. Results: Median ARF6 expression was higher in metastases (33.69 transcriptions per million) compared to primary/local tumors (27.59, q<.05). Specific metastatic sites showed higher expression than did primary tumors (q<.05 for liver and p<.05 for skin, bone and lymph nodes). Dividing into quartiles by ARF6 expression (the highest expression quartile, QH; the lowest, QL), KRAS mutations were significantly more prevalent in QH than QL (93.4 vs 87.2%, q<.05), and TP53 mutations had similar trends (81.0% in QH vs 74.7% in QL, p=.0078). The mutation rates of KDM6A, FANCD2 and TFEB amplifications trended higher in QH than QL; the STK11 mutation rate tended to be lower in QH (p<.05). PD-L1 expression by IHC was significantly higher in QH than QL (20.9 vs 13.1%); immune checkpoint genes by RNA expression: IFNG, IDO1, PDCD1G2, CD274, PDCD1 and PDCD2L were significantly higher in QH than QL (all q<.05). Macrophages, neutrophils, NK cells, fibroblasts and endothelial cells were more abundant in QH than QL (all q<.05); whereas CD4+ and CD8+ T cells were lower in QH (q<.05), and monocytes had similar trends (p<.05). High expression of ARF6 was significantly associated with unfavorable outcomes in OS (HR = 1.83, 95% CI [1.51–2.22], p<.0001); the effect on OS was seen when primary (HR = 1.47, [1.06–2.05], p=.02) and metastatic tumors (HR = 0.608, [1.29–2.10], p<.0001) were investigated separately. Conclusions: This is the first report showing that high gene expression of ARF6 in PDAC indicates a different immune profile, is enriched in cancer metastases, and is associated with poor survival. Our results provide the first clinical evidence supporting the ARF6 pathway as a major downstream target of KRAS and TP53 mutations promoting immune evasion, suggesting ARF6 is a novel marker for prognosis and a potential target for immune therapeutic strategies in PDAC.