BACKGROUND: Recommendations for intraoperative and postoperative breast sentinel lymph node (SLN) processing differ widely. Micrometastases and isolated tumor cells (ITC) have recently been proposed as prognostically and therapeutically relevant. We compared 3 SLN protocols with regard to intraoperative and postoperative diagnosis. MATERIALS AND METHODS: SLN in cohort I (270 patients) were intraoperatively assessed by stereomicroscopy. Intraoperative frozen section (IFS) was used only in stereomicroscopically suspicious SLN. In cohort II (197 patients), all SLN were examined with only 1 IFS. Final SLN workup in cohorts I and II consisted of complete step sectioning with immunohistochemistry. In cohort III (268 patients) 2 or more IFS were performed followed by 3 step sections and immunohistochemistry. RESULTS: pN1 stages were significantly higher in cohorts I and II (33.3% and 34.0% respectively) than in cohort III (24.6%). Intraoperative false negativity for the detection of metastases (pN1) ranged from 54.4% (cohort I) and 35.8% (cohort II) to 21.2% (cohort III). In contrast, ITC were detected significantly more frequently in cohort I (9.3%) and cohort II (14.7%) than in cohort III (1.9%). CONCLUSIONS: Higher rates of SLN metastases and ITC in cohort I/II compared to cohort III suggest that IFS may result in tissue loss thus increasing the risk of missing metastases. Sparse IFS but complete postoperative SLN workup with step sectioning and immunohistochemistry provides more accurate information regarding minimal disease in SLN, but often results in delayed axillary lymph node dissection. This is important for preoperative patient information and recommendations in SLN processing protocols.