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Aims We compared histological patterns after lumpectomy for non-palpable breast cancers preoperatively localized by radioguided occult lesion localization plus sentinel node localization (SNOLL) versus wire-guided localization. Methods To ensure a homogeneously treated cohort and rigorous comparisons, only patients with invasive cancer and measurable opacity by imaging were included. Exclusion criteria were one or more parameters that could interfere with localization and/or the surgical procedure. Forty-three SNOLL were compared with 86 WGL plus sentinel node (SN) localization. Cancer localization effectiveness was based on careful assessment of histological data from only the first resected glandular specimen, as any additional resection specimens were guided by intraoperative histological examination. Results Reexcisions to ensure free tissue margins were performed during the same procedure in 13.9% of SNOLL versus 31.3% of WGL; p = 0.02. Significantly more women in SNOLL (53.4%) also had free nearest margins of >9 mm after the first procedure compared with WGL (33.7%); p = 0.03. The median centricity ratio after the first procedure was better in SNOLL (2.8, range 1.3–14) than WGL (5, range 1–50); p = 0.008. The median number of SN detected by lymphoscintigraphy was the same in SNOLL and WGL (1, range 0–9, vs. 1, range 0–8). Intraoperative SN detection by blue dye and/or gamma probe was successful for 97.6% of SNOLL versus 93% of WGL. Conclusion In this study, SNOLL was effective and safe, and this procedure significantly improved the rate of negative margins in the first specimen and the rate of reexcision for positive margins compared with WGL.