Background: The purpose of this study was to examine data on treatment efficacy, cosmesis and toxicities for the final analysis of the American Society of Breast Surgeons MammoSite® breast brachytherapy registry trial. Methods: A total of 1,449 cases of early-stage breast cancer underwent breast conserving therapy. The single-lumen MammoSite® device was used to deliver accelerated partial breast irradiation (APBI) (34 Gy in 3.4 Gy fractions). Of these, 1,255 cases (87 %) had invasive breast cancer (IBC) and 194 cases had DCIS. Median follow-up was 63.1 months with 45 % of all patients having follow-up of 6 years or longer. Results: There were 41 cases (2.8 %) that developed an ipsilateral breast tumor recurrence (IBTR) for a 5-year actuarial rate of 3.8 % (3.7 % for IBC and 4.1 % for DCIS). Tumor size (odds ratio [OR] = 1.1, p = 0.03) and estrogen receptor negativity (OR = 3.0, p = 0.0009) were associated with IBTR, while a trend was noted for positive margins (OR = 2.0, p = 0.06) and cautionary/unsuitable status compared with suitable status (OR = 1.8, p = 0.07). The percentage of patients with excellent/good cosmetic results at 60, 72, and 84 months was 91.3, 90.5, and 90.6 %, respectively. The overall rates of fat necrosis and infections remained low at 2.5 and 9.6 % with few late toxicity events beyond 2 years. The overall symptomatic seroma rate was 13.4 and 0.6 % beyond 2 years. Conclusions: The final analysis of treatment efficacy, cosmesis, and toxicity from the American Society of Breast Surgeons MammoSite® breast brachytherapy registry trial confirms previously noted excellent results and compares favorably with other forms of APBI with similar follow-up and to outcomes seen in selected patients treated with whole breast irradiation.