Purpose <p>The use of neoadjuvant systemic therapy for primary breast cancer can achieve tumor shrinkage, enabling less invasive surgical treatments, such as breast-conserving surgery instead of mastectomy, and sentinel node biopsy instead of axillary dissection. In recent years, an increasing number of studies have explored the use of primary systemic therapy for occult breast cancer with axillary presentation. These studies suggest that a more conservative approach, involving targeted axillary surgery could be cautiously proposed for occult breast cancer after neoadjuvant chemotherapy in selected patients. In cases where a complete pathological response in the lymph nodes is achieved, there may also be the possibility to omit radiotherapy.</p> Methods <p>We retrospectively reviewed surgical interventions for carcinoma of unknown primary (CUP) syndrome with axillary presentation at the European Institute of Oncology from April 2004 to October 2022. Demographic and clinicopathological characteristics of the patients were collected and follow-up information has been updated.</p> Results <p>A total of 114 patients who underwent axillary surgery for occult breast cancer were included. The 5-year disease-free survival was 74.5%, while overall survival was 88.5%. A total of 22.8% of patients underwent neoadjuvant treatment. Complete pathological response was achieved in 38.5%. Patients with complete nodal pathological response showed fewer events compared to patients with no complete pathological response after neoadjuvant treatment.</p> Conclusion <p>Although the sample size is limited, recent advances in breast cancer multimodal treatment indicate that targeted axillary surgery may be considered for the rare clinical presentation of occult breast cancer after neoadjuvant treatment.</p> Trial registry <p>Trial registration number UID 4184 24/07/2024 “retrospectively registered”</p>