There are few studies focus on post-neoadjuvant treatment in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-)/lymph node-positive (LN+) breast cancer, a multi-center, open-label, randomized, controlled phase III trial was conducted to evaluate pathological response-guided non-cross-resistant adjuvant chemotherapy in patients with HR+/HER2-/LN+ breast cancer who were non-responsive to primary chemotherapy. Patients received four cycles of non-cross-resistant adjuvant chemotherapy plus endocrine therapy (ET), or ET alone. Forty patients responsive to neoadjuvant chemotherapy and with Miller and Payne G4 or G5 and LN- status were assigned to the observation group. Distant disease-free survival was the primary endpoint. The final intention-to-treat analysis comprised 379 patients. After a median follow-up period of 72.4 months, the 5-year distant disease-free survival was 92% and 90% in the chemotherapy plus ET and ET-alone groups, respectively. Comparatively, the observation group showed a trend towards better distant disease-free survival. For patients non-responsive to neoadjuvant chemotherapy, adjuvant non-cross-resistant chemotherapy did not significantly improve distant disease-free survival compared to ET alone.