The chemokine stromal cell-derived factor (SDF-1/CXCL12) and its specific receptor, CXCR4, have been implicated in the regulation of tumor growth and organ-specific spread. The aim of this study was to determine the expression of CXCL12 and CXCR4 in samples obtained from primary squamous cell carcinoma (SCC) of the oral cavity (OCSCC) and of the lip (LSCC) and in metastatic and non-metastatic lymph node tissues. The relationship of CXCL12/CXCR4 with clinical and microscopic parameters was also evaluated. The analysis of mRNA expression revealed a higher expression of CXCR4 in oral SCC compared with healthy oral mucosa (p = 0.006). The density of CXCR4+ cells was higher in parenchyma of OCSCC with lymph node metastases than in LSCC. With regard to the stroma, OCSCC showed a greater CXCR4+ and CXCL12+ cell percentage in relation to LSCC. Furthermore, the density of CXCL12+ and CXCR4+ nodal cells was higher in metastatic than non-metastatic lymph nodes in the same patients. Considering clinical and microscopic parameters, we found a positive association between the percentages of CXCL12+ and CXCR4+ stromal cells and the tumor proliferation index. Our findings suggest that the CXCL12/CXCR4 system may play a role in tumor cell spread to lymph nodes and also in neoplastic development. (c) 2008 S. Karger AG, Basel.