We studied whether precursor lesions (monomorphic epithelial proliferations [MEPs]) contributed to ipsilateral breast failures (IBFs; local recurrences). Margin status and MEPs near (within 4.2 mm) of the initial excision margin in 70 carcinoma patients with IBFs and allelic imbalance clonality data were recorded. Of the IBFs, 46 (66%) were clonal and 24 (34%) were second primary carcinomas. Control cases were 2 matching non-IBF cases for each study case. MEP lesions were predominantly single-cell layered, slightly overcrowded, monomorphic, clonallike luminal cell proliferations that unfolded terminal duct lobular units (TDLUs) in an overgrowth extension pattern. MEPs often extended into TDLUs involved by hyperplasia of usual type. Clonal IBF cases had a mean of 6.24 MEPs near the initial excision margin compared with 3.85 MEPs in matched non-IBF control mples (P < .001). In the negative-margin subset, clonal IBF cases had mean of 7.82 MEPs near the margin, which was significantly greater than 4.26 in the distinct IBF group (P = .012) and 2.85 in the non-IBF matched control group (P < .001). MEPs seem to be the pool of partially transformed precursor lesions for most invasive carcinomas. Radiation therapy may reduce the IBF rate by eradicating these precursor lesions and preventing new carcinomas from emerging rather than eradicating microscopic residual disease.