The implications of Phosphatidylinositol 3-kinase (PIK3CA) mutations and its aberrant protein expression in breast cancer (BC) different molecular subtypes and patients' outcome remain controversial. The aims of this study were to assess the prevalence and clinical significance of PIK3CA protein expression in BC and to determine its association with its different molecular classes. PIK3CA protein expression was assessed in a well-characterized series of early stage BC (n = 1,394) with long-term follow-up, using tissue microarrays and immunohistochemistry. Associations between PIK3CA expression and clinicopathological variables, molecular classes, and patients' outcome were investigated. Positive PIK3CA expression was associated with poor prognostic variables including higher grade, larger size, nodal involvement, vascular invasion, and higher proliferative fraction (P < 0.001). Increased PIK3CA expression was associated with the basal-like breast cancer (BLBC) and HER2-positive classes as well as triple negative non-basal (TNnon-B) tumors (P < 0.001). The luminal class showed reduced PIK3CA expression relative to other classes. Patients with PIK3CA positive tumors had shorter BC specific and disease free survival, independent of other prognostic factors except grade. Similar associations with outcome were found when the analysis was restricted to the large luminal class of tumors. PIK3CA is an oncogenic biomarker associated with poor prognosis in BC. Although, PIK3CA over-expression was more prevalent in BLBC and HER2-positive tumors it appeared to be a marker of poor differentiation rather than of a particular subtype. Thus, targeting of PIK3CA using specific inhibitors could potentially be beneficial, particularly for patients with more aggressive poorly differentiated tumors, irrespective of their molecular subtype.