Background: Low post-endocrine Ki67 (Ki67_post) as a marker for endocrine therapy response (ETR) has been shown to be a favorable prognostic factor in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (EBC). So far, all studies have used centralized immunohistochemical measurements. In order to assess the robustness of this marker for clinical routine, we have now compared local and central Ki67 measurements in the WSG ADAPTcycle trial. Patients and methods: In the WSG ADAPTcycle trial (n = 5292 screened, 1684 randomized; 85 sites in Germany), patients with intermediate-risk EBC based on Oncotype DX and ETR were randomized to (neo)adjuvant chemotherapy followed by endocrine therapy (ET) versus ribociclib + aromatase inhibitor (AI) (premenopausal: + gonadotropin-releasing hormone). Concordance of local and central Ki67 [baseline (BL), post-ET] was evaluated in the whole trial cohort and in different subgroups. Results: Median BL Ki67 values were 25% locally (n = 4972) and centrally (n = 4903). Overall agreement (OA) for Ki67 >10% versus ≤10% was 86.9% [95% confidence interval (CI) 85.9% to 87.9%]. After short preoperative ET, median local (n = 2786) and central (n = 4429) Ki67_post were 5% and 10%, respectively. ETR (Ki67_post ≤10%) was observed in 1663 patients (64.2%) centrally versus 1571 (60.7%) locally with an OA of 80.5% (95% CI 79% to 82.1%). While overall, among local ET responders, 206 (13.1%) were central non-responders, >90% concordance was seen in AI-treated patients. Conclusions: When comparing central and local Ki67 assessments in the large multicenter randomized WSG ADAPTcycle trial, we observed similar rates of ET responders. The agreement between local and central Ki67 assessments at BL and post-endocrine treatment was high, but not yet optimal, with the highest concordance observed in AI-treated patients. Incorporating ETR into daily clinical practice together with multigene assays (as used in WSG ADAPT and ADAPTcycle) needs to be supported by clinicopathological markers for therapy decision making and accompanied by quality assurance programs for Ki67 determination.