Summary Background Data: Previous studies have suggested a variety of factors that may affect the false negative (FN) rate for sentinel lymph node (SLN) biopsy in breast cancer. Because FN results are relatively rare, no prior studies have had sufficient sample size to allow detailed statistical analysis of factors predicting FN results. Methods: Patients with clinical stage T1-2, N0 invasive breast cancer were enrolled in a prospective, multicenter study. All patients underwent SLN biopsy, followed by planned completion axillary dissection regardless of the SLN results, to assess the FN rate. SLN biopsy was performed using radioactive colloid injection in combi-nation with isosulfan blue dye in 94% of cases. Dermal, subdermal, peritumoral, or subareolar radioactive colloid injection techniques were used at the discretion of each institution. Univariate and multivariate analyses were performed to identify factors associated with a FN result. Results: SLNs were identified in 3870 of 4117 patients (94%). There were 1243 true positive, 2521 true negative, and 106 FN results. Age, histologic subtype, the number of non-SLN removed, tumor palpability, type of breast biopsy, and SLN injection technique were not significant factors. On multivariate analysis, tumor size <2.5 cm, upper outer quadrant tumor location, removal of only a single SLN, minimal surgeon experience, presence of a single positive axillary LN, and use of immunohistochemistry (IHC) for SLN analysis were independently associated with an increased risk of FN results. Conclusions: Surgeon experience, tumor size and location, and the number of SLN removed are preoperative and intraoperative factors that independently predict the risk of a FN result. In contrast to suggestions from other smaller studies, age does not affect the likelihood of a FN result; a lesser, rather than greater, number of positive axillary nodes was associated with an increased likelihood of a FN result; and IHC analysis of the SLN increases, rather than decreases, the risk of FN results. Copyright © 2005 by Lippincott Williams & Wilkins.