Hypothesis: Subareolar or periareolar injection of radioactive technetium sulfur colloid is equivalent to other injection techniques for breast cancer sentinel lymph node (SLN) biopsy. Design and Setting: Prospective, multicenter clinical trial. Patients: A total of 3961 individuals with clinical stage I and II breast cancer. Interventions: All patients underwent attempted SLN biopsy followed by completion axillary dissection. Injection technique was determined by the preference of each participating surgeon. Most surgeons had little or no experience with SLN biopsy before participation in this study. Main Outcome Measures: The SLN identification and false-negative rates. Results: An SLN biopsy was performed in 3961 patients using blue dye alone or radioactive colloid plus blue dye. Subareolar and periareolar radioactive colloid injection techniques were associated with SLN identification rates of 99.3% and 95.6%, respectively, with false-negative rates of 8.3% and 8.9%, respectively. The identification rates were significantly higher for these 2 techniques than for peritumoral injection of radioactive colloid (91.1%) or the use of blue dye alone (88.5%) (P<.001). The false-negative rates were similar for all techniques. Conclusions: Although many medical centers have adopted subareolar and periareolar radioactive colloid injections because of their simplicity and convenience, a paucity of data from a few single-institutional studies has existed to substantiate the false-negative rates associated with these techniques. The results of this multicenter study establish the validity of subareolar and periareolar radioactive colloid injections and support the hypothesis that the lymphatic drainage of the entire breast is to the same few SLNs.