Background: The presence of circulating tumor cells (CTCs) before chemotherapy (CTX) is an independent prognostic marker for reduced survival in early breast cancer (EBC). In addition, recent results suggest that persisting CTCs immediately after adjuvant CTX indicate poor prognosis. There is a lack of data regarding the best use of CTC numbers for risk stratification. Here, we evaluated different methods to calculate changes in CTC counts during the course of CTX and their prognostic value with respect to overall survival (OS). Methods: The German SUCCESS A trial is a phase III study in which patients with high-risk EBC were first randomized to adjuvant CTX treatment with 3 cycles of epirubicin-fluorouracil-cyclophosphamide followed by either 3 cycles of docetaxel or 3 cycles of gemcitabine-docetaxel. CTC enumeration was performed using the FDA-approved CellSearch System (Janssen Diagnostics, LLC). Patient outcome in terms of OS was analyzed using univariate log-rank tests and Cox regression models. Information on CTC status before and after CTX was available for 1507 (40.1 %) of 3754 randomized patients. Results: Overall, 311 patients had at least one CTC before CTX (median 1 CTC, range 1 – 827) and were included in the analyses. 79 (25.4%) of these patients had at least one CTC after CTX (median 1, range 1 – 124). A quantitative assessment with the change in number of CTCs (before and after CTX) as continuous variable significantly predicted OS (hazard ratio [HR] 0.995, 95% confidence interval [CI] 0.992-0.998, p = 0.002). Surprisingly CTC clearance (no vs. yes) was not significantly associated with OS (HR 1.508, 95% CI 0.783- 2.904, p = 0.216). However, patients that showed an increase in CTC number from before to after CTX had significantly shorter OS than patients with no such increase (HR 3.545, 95% CI 1.490- 8.434, p = 0.004). Conclusions: Both a quantitative assessment in terms of changes in CTC numbers from before to after CTX and a qualitative measure according to whether or not there was an increase in CTC number showed a significant association with overall survival in EBC patients. Clinical trial information: NCT02181101