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Although sentinel lymph node (SLN) biopsy is widely accepted as a minimally invasive method of nodal staging, failure to identify an SLN mandates a level I/II axillary node dissection. The purpose of this study was to elucidate factors that independently predict failure to identify an SLN.Using a large multicenter prospective study of SLN biopsy for patients with invasive breast cancer, we performed univariate and multivariate regression analyses to determine clinicopathologic factors predictive of failure to identify an SLN.Of the total 4131 patients in the study, an SLN was not identified in 249 (6.0%). Tumor location (P = .409), biopsy type (P = .079), surgery type (P = .380), and histologic subtype (P = .999) were not significant predictors of failure to identify an SLN. On multivariate analysis, age greater than 60 years (OR = 1.469; 95% CI, 1.116–1.934, P = .006), nonpalpable tumors (OR = 0.639; 95% CI, 0.479–0.852, P = .002), injection technique with blue dye alone (OR = 0.389, 95% CI, 0.259–5.86, P < .001), and surgical experience of less than 10 SLN biopsy cases (OR = 1.886; 1.428–2.492, P < .001) were significant independent predictors of failure to identify an SLN. Optimal SLN biopsy technique using an intradermal and/or subareolar injection of radioactive colloid and blue dye can improve SLN identification rates regardless of patient and tumor characteristics.Patient age and tumor palpability significantly affect the ability to identify an SLN in patients with breast cancer. Optimal injection technique can significantly improve sentinel node identification rate regardless of these factors.