CXC chemokine receptor 4 (CXCR4) has been reported to be involved in organ-specific homing of breast cancer-derived metastasis. We investigated CXCR4 expression by immunohistochemistry as a possible new prognostic factor for primary breast cancer. Two groups of women treated for breast cancer in 1991 at the Centre for the fight against cancer of Upper Normandy-France (Centre de Lutte contre le Cancer de Haute Normandie) were assessed retrospectively. CXCR4 expression was evaluated using standard immunohistochemistry. Usual prognostic factors were recorded in the computer database. Final date of follow-up was December 31, 2001. Tissues were available for 110 node-positive and 84 node-negative breast cancer patients treated in 1991. CXCR4 membrane staining was considered a strong prognostic factor for both 10-year metastasis-free- (p < 0.0001) and overall survival (p < 0.0001) in node-negative but not in node-positive breast cancer patients. CXCR4 cytoplasmic staining was not considered a significant prognostic factor. Our results suggest that CXCR4 membrane staining could be considered a new prognostic factor. Moreover, targeting CXCR4 in primary breast cancer patients may be a new therapeutic concept. However, these results warrant further investigation.