Background The Z0011 trial initiated a paradigm shift in the axillary treatment of breast cancer patients with a positive sentinel lymph node biopsy (SLNB), disregarding patients with a positive ultrasound-guided lymph node biopsy (UGLNB). We examined whether relevant differences exist between these patients to determine if the conclusions of the ACOSOG Z0011 trial are applicable to UGLNB-positive patients. Methods Patients diagnosed with invasive breast cancer in the Netherlands between January 2008 and December 2014 were selected from the Netherlands Cancer Registry. Results A total of 11,820 cases were included: 9149 cases in the SLNB group and 2671 in the UGLNB group. Multivariate analyses showed that UGLNB-positive patients were older ( p  < 0.001), more likely to have a poorly differentiated tumor ( p  < 0.001), had a negative hormone receptor status ( p  < 0.001), and more often had extensive nodal involvement ( p  < 0.001). However, they were less likely to undergo adjuvant radiation ( p  = 0.004) or systemic therapy ( p  < 0.001). Even after adjusting for these factors, UGLNB-positive patients had a worse overall survival (HR = 1.38; 95% CI 1.23–1.56) than SLNB-positive patients. Conclusion This nationwide retrospective study shows that young patients found positive by UGLNB have less favorable disease characteristics and a worse prognosis compared to patients with a positive SLNB. Selection by ultrasound plays an important role when axillary treatment strategies are considered. Hence, the conclusions of the Z0011 trial cannot unconditionally be applied to patients with a positive UGLNB.