Background: Current guidelines for APBI stratify appropriateness of treatment outside of a clinical trial. Limited data are available, however, regarding the impact of the number of risk factors (RFs) per patient on clinical outcomes. Methods: 692 patients were treated with APBI at a single institution between 10/1992 and 10/2011. Patients were stratified by the ASTRO guidelines as suitable, cautionary, and unsuitable. Outcomes including ipsilateral/contralateral breast tumor recurrence (IBTR/CBTR), regional recurrence (RR), distant metastases (DM), disease-free survival (DFS), cause specific survival (CSS), and overall survival (OS) were evaluated by risk group and number of RFs. Results: Median follow-up was 5.2 years (range: 0-18.3).Distribution within CP risk-groups was suitable: 240, cautionary: 343, and unsuitable: 109 patients. Increased IBTR (2.0% v. 0.6%, p=0.03), DM (6.5% v. 1.5%, p=0.02), and decreased DFS (92% v. 98%, p=0.01) were noted for patients with 2+ cautionary RFs (n=115) vs. 1 RF (n=228). Those with 2+ unsuitable RFs had higher RR (7.7% v. 1.7%, p=0.05). Pooled analysis revealed increased IBTR/RR for patients with 3+ combined cautionary/unsuitable RFs vs. 2 or fewer combined RFs (Table). Univariate analysis showed increased DM with increasing tumor size/T-stage (p<0.01), ER negativity (p=0.04), LVSI (p=0.01), + LN (p<0.01), and increasing number of RFs (p<0.01). No single RF was associated with an increased risk of local recurrence on UVA. Conclusions: Three or more cautionary or unsuitable APBI RFs is associated with higher local, regional, and distant recurrence. Patients with fewer than 3 total RFs have a 98% locoregional control at 5 years and likely remain good candidates for APBI. Future attempts to risk stratify patients may need to account for the number of RF present in order to appropriately classify patients.