© 2020 American Association for Cancer Research. Purpose: The purpose of this study is to predict risk of local recurrence (LR) in ductal carcinoma in situ (DCIS) with a new visualization and quantiﬁcation approach using centrosome ampliﬁcation (CA), a cancer cell-speciﬁc trait widely associated with aggressiveness. Experimental Design: This ﬁrst-of-its-kind methodology evaluates the severity and frequency of numerical and structural CA present within DCIS and assigns a quantitative centrosomal ampliﬁcation score (CAS) to each sample. Analyses were performed in a discovery cohort (DC, n ¼ 133) and a validation cohort (VC, n ¼ 119). Results: DCIS cases with LR exhibited signiﬁcantly higher CAS than recurrence-free cases. Higher CAS was associated with a greater risk of developing LR (HR, 6.3 and 4.8 for DC and VC, respectively; P < 0.001). CAS remained an independent predictor of relapse-free survival (HR, 7.4 and 4.5 for DC and VC, respectively; P < 0.001) even after accounting for potentially confounding factors [grade, age, comedo necrosis, and radiotherapy (RT)]. Patient stratiﬁcation using CAS (P < 0.0001) was superior to that by Van Nuys Prognostic Index (VNPI; HR for CAS ¼ 6.2 vs. HR for VNPI ¼ 1.1). Among patients treated with breast-conserving surgery alone, CAS identiﬁed patients likely to beneﬁt from adjuvant RT. Conclusions: CAS predicted 10-year LR risk for patients who underwent surgical management alone and identiﬁed patients who may be at low risk of recurrence, and for whom adjuvant RT may not be required. CAS demonstrated the highest concordance among the known prognostic models such as VNPI and clinicopathologic variables such as grade, age, and comedo necrosis.