Most patients with early-stage breast cancer are treated with adjuvant radiotherapy (RT) after breast-conserving surgery (BCS) to prevent locoregional recurrence (LRR). However, no genomic tools are used currently to select the optimal RT strategy. We profiled the transcriptome of primary tumors on a clinical grade assay from the SweBCG91-RT trial, in which patients with node-negative breast cancer were randomly assigned to either whole-breast RT after BCS or no RT. We derived a new classifier, Adjuvant Radiotherapy Intensification Classifier (ARTIC), comprising 27 genes and patient age, in three publicly available cohorts, then independently validated ARTIC for LRR in 748 patients in SweBCG91-RT. We also compared previously published genomic signatures for ability to predict benefit from RT in SweBCG91-RT. ARTIC was highly prognostic for LRR in patients treated with RT (hazard ratio HR, 3.4; 95% CI, 2.0 to 5.9; < .001) and predictive of RT benefit ( = .005). Patients with low ARTIC scores had a large benefit from RT (HR, 0.33 95% CI, 0.21 to 0.52, < .001; 10-year cumulative incidence of LRR, 6% 21%), whereas those with high ARTIC scores benefited less from RT (HR, 0.73 95% CI, 0.44 to 1.2, = .23; 10-year cumulative incidence of LRR, 25% 32%). In contrast, none of the eight previously published signatures were predictive of benefit from RT in SweBCG91-RT. ARTIC identified women with a substantial benefit from RT as well as women with a particularly elevated LRR risk in whom whole-breast RT was not sufficiently effective and, thus, in whom intensified treatment strategies such as tumor-bed boost, and possibly regional nodal RT, should be considered. To our knowledge, ARTIC is the first classifier validated as predictive of benefit from RT in a phase III clinical trial with patients randomly assigned to receive or not receive RT.