Background: Circadian rhythms regulate the cellular and molecular processes that determine treatment effects. Scarce data suggest that daily timing could influence endocrine therapy (ET) pharmacology. We prospectively tested this hypothesis within the UNIRAD adjuvant phase III trial (NCT01805271) in patients (pts) with hormone receptors positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC). Methods: Between June 2013 and March 2020, 1,278 pts with high-risk HR+/HER2- primary BC were randomly assigned to adjuvant ET combined with EVE or placebo. Pts were stratified according to lymph node involvement, progesterone receptor status, ET (tamoxifen or aromatase inhibitors (AI)), prior neoadjuvant or adjuvant chemotherapy, and duration of ET before randomization. Throughout their participation in the trial, patients were asked to declare prospectively in a daily diary the timing of ET intake within four 6-h slots (06:00 to11:59 (morning), 12:00 to 17:59 (afternoon), 18:00 to 23:59 (evening), or 24:00 to 05:59 (night). The prognostic impact of the timing of ET and EVE/placebo on DFS was a prespecified secondary endpoint. Results: A total of 855 patients (67%) recorded ET intake daily timings (n = 401 in the EVE arm, n = 454 in the placebo arm). Morning intake was preferred by 465 pts (54%), whilst 344 pts (40%) chose evening intake, and minor proportions took ET in the afternoon (49 patients, 5%) or at night (5 patients, 1%). Pts choosing morning or afternoon intake were significantly older than those preferring evening or night intakes (mean age: morning: 56.4 y.o.; afternoon: 58.4 y.o; evening: 53.1 y.o ; night : 50.8 y.o.; p < 0.001). Only 10 patients (1.1%) reported changing ET timing during the study. With a median follow-up of 72.5 months, 118 patients relapsed (locally n = 30, metastases n = 84), and 41 patients died. In the whole population, ET intake timing was not associated with DFS (HR 0.77 [95%CI, 0.53-1.12], p = 0.17). ET intake timing effects according to the stratification factors revealed a significant interaction between its prognostic impact and ET agent (tamoxifen versus AI, p for interaction = 0.01). DFS was prolonged in those pts taking tamoxifen in the evening/night rather than in the morning/afternoon (HR = 0.43 [0.22 - 0.85], p = 0.015), while no such effect was found for those on AI (HR = 1.07 [0.68 - 1.7], p = 0.761). Such interaction remained statistically significant at multivariate analysis (HR 0.38, p = 0.003). Conclusions: Tamoxifen intake in the evening was associated with an improved DFS in high-risk HR+/HER2- breast cancer pts and could be recommended at no cost in the adjuvant setting. Clinical trial information: NCT01805271.