Measuring CA15.3 serum levels in the early breast cancer setting is not recommended by current ASCO guidelines. In this large single center study, we assess the prognostic value of preoperative (n = 3746), postoperative (n = 4049) and change in (n = 3252) CA15.3, also across different breast cancer phenotypes. Preoperative, postoperative and change in CA15.3 were all significant (p = 0.0348, p < 0.0001, p < 0.0001 respectively in multivariate analysis) predictors of distant metastasis free survival. For breast cancer specific survival, only postoperative and change in CA15.3 were significant predictors (p < 0.0001 both). Multivariate prognostic models did not improve by incorporating information on preoperative CA15.3, but did improve when introducing information on postoperative CA15.3 for distant metastasis (p = 0.0365) and on change in CA15.3 for breast cancer specific survival (p = 0.0291). Change in CA15.3 impacts on prognosis (distant metastasis) differently in different breast cancer phenotypes. A decrease in CA15.3 may be informative of improved prognosis in basal like and HER2 like breast cancer.