Purpose We report the long-term results of phase II prospective study with accelerated partial breast irradiation (APBI) using interstitial multi-catheter high-dose-rate brachytherapy. Methods 240 patients received APBI (4 Gy, twice daily; total dose 32 Gy). Results Median follow-up was 96 months. Recurrences in the treated breast developed in 8 patients (3.3%) at a median of 73 months after APBI. The 5- and 10-year cumulative incidences were respectively, 1.8% (95%CI: 0.6–4.3) and 6.6% (95%CI: 2.7–12.9). Regional recurrences developed in 5 patients (2%) at a median of 28 months and distant metastases in 8 (3.3%) at a median of 32.5 months. Breast cancer specific mortality occurred in 6 patients (2.5%) at a median of 60 months. Acute toxicity developed in 71 (29.6%) patients (G1 in 60 and G2 in 11). Almost all were skin toxicity and hematomas. Late toxicity was observed in 90 patients (37.5%), G1 in 97 cases and G2 in 11. Some patients presented with more than one type of toxicity. Teleangectasia and fibrosis were the most common (48 and 44 cases respectively), followed by fat necrosis (in 18 patients) Tamoxifen emerged as the only risk factor for breast fibrosis (p = 0.007). Cosmetic results were judged by the physicians as excellent in 174 (83.7%) patients, good in 25 (12%) fair in 8 (3.8%) and poor in 1 (0.5%); 174 patients (83.7%) judged outcomes as excellent, 26 (12.4%) as good, 7 (3.4%) as fair and 1 (0.5%) as poor. Physician/patient agreement was good (weighted k-value 0.72). Conclusions APBI with interstitial multi-catheter brachytherapy was associated with good outcomes, low relapse and toxicity rates. Few events during this long-term follow-up preclude identifying specific features of patients at risk of relapse and illustrate the need for a large data-base.