Apolipoprotein D (ApoD) is a lipocalin involved in various cellular processes, including cytoprotection. We retrospectively evaluated its prognostic impact in 272 women (median age 63 (range 21-89) years, with operable breast cancer (Stage I or IIa) treated according to national guidelines, stratified by age and menopausal status, with a median long-term follow-up of 12 years. ApoD, estrogen receptor-alpha (ERalpha), and progesterone receptor (PR) positivity were determined by quantitative immunohistochemistry in tissue microarrays taken from the invasive front of the tumors and in whole tumor sections. ApoD was expressed in 50% of the tumors. Diffuse nuclear and cytoplasmic (ApoD(CN)), but not granular cytoplasmic ApoD expression in the invasive front was a detrimental factor for elderly patients over 70 years of age, (n = 83), but not for younger and pre-menopausal patients. ApoD(CN )expression correlated with lymph node metastases (P = 0.04). Moreover, a correlation between ApoD(CN )localization and age over 70 years was observed (P = 0.03). In the elderly, ApoD(CN) positive tumors had both a significantly shorter relapse-free survival (all locations) (P = 0.02) and a decreased breast cancer-specific survival (P < 0.0001). Moreover, the prognostic importance of ApoD was dose dependent (P = 0.002) Multivariate analysis confirmed the prognostic value of ApoD(CN). When the elderly patients were stratified by nodal status, ApoD showed prognostic importance only in the node positive patients (n = 30) (HR = 9.6; 95% CI = 2.3-40.4). The potential relevance of ApoD in this increasingly frequent group of breast cancer patients should be further explored.