Background: We recently showed in an aromatase-gene transfected breast cancer cell line, a radiosensitizing effect of letrozole. We then conducted a multicentric phase II randomized trial evaluating adjuvant concomitant radiotherapy and letrozole with radiotherapy followed by letrozole in postmenopausal early breast cancer patients (CO-HO-RT trial). Methods: Postmenopausal pts with early stage breast cancer were randomized after conservative surgery to either: A) concurrent RT-LET (LET started 3 weeks before the first day of RT) or B) sequential RT-LET (LET started 3 weeks after the end of RT). Whole breast RT was delivered to a total dose of 50 Gy ± a 10-16 Gy boost. Pts were stratified by center, adjuvant chemotherapy (ACT), boost, CD8 radiation-induced apoptosis. Primary endpoint was radiation-induced acute and late skin toxicity. Skin toxicities were evaluated by two different clinicians at each medical visit (CTCAE v3.0). Lung CT-scan and functional pulmonary tests were performed regularly. Quality of life and cosmetic assessments were registered. DNA samples were screened for SNPs in the ATM genes. Results: A total of 150 pts were randomized between 01/05 and 02/07. Median follow-up was 17 months (range, 6-49). No statistical differences were identified between the two arms in terms of mean age; initial TNM; median surgical bed volume; postsurgical breast volume. ACT and RT boost were delivered in 19% and 38% of pts, respectively. Overall, 10 patients (6.7%) presented grade 3 acute skin dermatitis during RT without differences between both arms. Grade 2 acute skin dermatitis was observed in 36.5% and 32% in arm A and B, respectively, but symptoms rapidly settled in most patients by months 3, 6, and 12. Grade 2 radiation-induced subcutaneous fibrosis was found in 8 patients (5%) with a slight difference in disfavor of arm B (7%) vs 4% in arm A. Three patients (2%) presented a grade 2 pneumonitis (all in arm A). Overall, quality of life and cosmesis were good to excellent. Conclusions: Concurrent or sequential adjuvant radiohormonotherapy with letrozole is feasible in daily practice. Identifying hypersensitive patients with CD8 RIA or ATM screening will help tailoring treatments.