Abstract Background Randomized trials have progressively enabled the de-escalation of axillary surgery in breast cancer (BC) patients, reducing adverse events without compromising survival. Despite a not negligible rate of residual disease in the axilla after sentinel lymph node (SLN) procedure, the risk of regional lymph node recurrence (RLNR) is very low, due probably to multimodal adjuvant treatments. The characteristics of the small number of patients with RLNR remain poorly characterized and warrant further investigation, especially given their poor prognosis and the current context of ongoing studies exploring further de-escalation of axillary surgery. Methods In this retrospective and single institution study, we analyzed thoroughly a cohort of patients who experienced RLNR as first event between 2009 and 2020. MammaPrint and BluePrint analysis (MB) was performed in available primary invasive cancer tissues. Results Forty patients, median age of 52, were analyzed. Disease-free interval was 8.7 years. Most of the patients (65%) had no special type BC. Majority (73%) had hormone receptor positive-HER2 negative (HR + /HER2−) BC, 13% triple negative (TNBC), 6% HER2 + , 8% ductal carcinoma in situ and 3% unknown. The median size of the primary tumor was 1.8 cm (range 0.3–7.0) and 57% had no initial LN involvement. Forty five percent had primary SLN procedure and 53% axillary LN dissection (ALND) of the patients received neo-/adjuvant chemotherapy, 63% endocrine therapy and 68% radiotherapy (50% only in breast). Sixty three percent had only RLNR and 38% had concomitant distant metastases. Among irradiated patients, 63% had some relapse in the radiation field. The MB analysis classified 70% of the analyzed cancers as low-risk luminal A (82% in HR + /HER2−), 15% high-risk luminal B, 10% high-risk basal type, and 5% high-risk HER2 type. Conclusion Our study confirms that patients treated with SLN do not show a higher risk of LRNR compared to ALND. LRNR is often diagnosed incidentally. Younger age, residual disease post-NAC, no regional radiation, stage II, and initial LN involvement were more represented, as well as patients with endocrine sensitive disease classified as low-risk luminal A by MB. Ongoing trials, including SOUND, INSEMA, and BOOG 2013-08, are further exploring axillary surgery de-escalation.