Dysregulation of the chemokine receptor CXCR4 is relevant in melanoma progression, and the CXCR4/CXCL12 axis has been shown to activate cell cycle progression and malignant cell migration through stimulation of the mitogen-activated protein kinase pathway. Studies ascertaining the potential utility of CXCR4 mRNA as a prognosticator in melanoma have focused mainly on metastatic melanoma with conflicting results. In the light of this, we sought to explore the potential relationship between CXCR4 mRNA expression with established histopathologic prognosticators and BRAF status in melanoma. Archived consecutive samples (n=107) of primary cutaneous melanoma were retrieved and assessed for the following: CXCR4 mRNA (semiquantitative RT-PCR) and BRAF exon 15 status (DNA Sanger sequencing). Statistical analyses included correlation between CXCR4 mRNA levels and established histopathologic prognosticators as well as the BRAF status using univariate and multiple linear methods. Multivariable analyses revealed a significant correlation between elevated CXCR4 mRNA (low ΔCt value) and the presence of BRAF mutation (P=0.02). Absence of a brisk host response was associated with elevated CXCR4 mRNA expression (P=0.04). CXCR4 mRNA was significantly lower in AJCC stage 2 compared with stage 1 after controlling for significant clinical prognosticators (P=0.02). The association between elevated CXCR4 mRNA and absence of a brisk host response suggests that CXCR4 may be involved in regulation of the host immune response in melanoma and is a molecule of potential utility as a biomarker for recruiting melanoma patients for immunotherapy. Higher CXCR4 mRNA in patients with a BRAF mutation suggests its utility as a putative therapeutic target.