BACKGROUND Previous studies have established cross-talk between CXC chemokine receptor 4 (CXCR4) and epidermal growth factor receptor (EGFR) in gastric cancer, however, the effect of dual CXCR4/EGFR tumor status on patient survival and mechanisms regulating expression has yet to be investigated. MATERIAL AND METHODS A total of 56 gastric cancer patients were recruited to reveal the relationship between CXCR4 and EGFR expression, and the clinic-pathological features of samples were investigated by immunohistochemical staining. Two gastric cancer cell lines were treated with CXCL12 or EGF, and expression levels of CXCR4 and EGFR were detected by reverse-transcription-polymerase chain reaction and western blotting. Cells were treated with an NF-kappaB pathway inhibitor to investigate its role in the regulation of CXCL12 or EGF-mediated CXCR4 and EGFR expression and migration ability. RESULTS The results show that CXCL12 upregulated CXCR4 and EGFR. Similarly, EGF could induce the expression of CXCR4 and contribute to gastric cancer cell metastasis. In addition, both CXCL12 and EGF could induce the activation of IKKalphaß and P65. Conversely, suppression of the NF-kappaB pathway remarkably decreased the expression of CXCR4/EGFR and migration ability induced by EGF or CXCL12. Furthermore, a significantly positive correlation between CXCR4 and EGFR expression was observed in gastric cancer patient tissues (r=0.372, P=0.005). Samples expressing both receptors had significantly poorer patient prognosis than other patient groups (P=0.002). CONCLUSIONS Our results showed that the CXCL12/CXCR4 and EGF/EGFR axis can regulate the expression of each other through the NF-kappaB pathway to promote metastasis. These data suggested that simultaneous inhibition of EGFR and CXCR4 may be a potential therapeutic strategy in gastric cancer.