To determine the significance of (Cyclooxygenase 2) COX2 for clinical outcome in breast cancer, we analyzed the correlation between COX2 overexpression and survival in 687 patients with invasive breast cancer. Cytoplasmic immunoreactivity of COX2 was determined as positive in 325 of 687 (47.3%) invasive breast cancers. COX2 positivity was significantly correlated with high histologic grade, negative estrogen receptor (ER), high Ki67, luminal B and triple-negative tumors, Bcl2 negativity, and p53 overexpression. In univariate analysis, COX2 overexpression resulted in significantly shorter relapse-free survival (RFS) [hazard ratio (HR) 1.487, 95% CI 1.035-2.110, P = 0.032]. Multivariate analysis revealed no significant association between COX2 overexpression and either overall survival (OS) or RFS. Kaplan-Meier analysis of the whole patient group showed significantly reduced RFS in patients with high COX2 expression, compared to those that did not overexpress COX2 (91 vs. 162 months, P = 0.031). Stratified subgroup analysis by TNM stage disclosed marked differences in OS and RFS rates in Stage III patients. We observed a significant association of COX2 overexpression with shorter RFS in the ER-negative subgroup of Stage III patients. The results show that COX2 overexpression is a significant unfavorable prognostic factor in Stage III breast cancer, and provide selective criteria for COX2 inhibitor combinations for invasive breast cancer therapy.