BACKGROUND: The role of microRNAs (miRs) in hormone therapy (HT) is of keen interest in developing biomarkers and treatments for individuals with breast cancer. Although miRs are often moderate regulators under homeostatic conditions, their function is changed more in response to physical activity. OBJECTIVE: This single-blind randomized trial aimed to explore the effect of high-intensity interval training (HIIT) on serum levels of miRs in individuals with early-stage breast cancer undergoing HT. METHODS: Hormone receptor-positive women with breast cancer and healthy women were randomly assigned to a healthy control group (n=15), healthy group with HIIT (n=15), breast cancer group with HT (HT, n=26), and breast cancer group with HT and HIIT (HT+HIIT, n=26). The exercise groups underwent interval uphill walking training on a treadmill 3 times a week for 12weeks. At the end of the study, we analyzed changes in levels of cancer-related miRs (oncomiRs) and tumour suppressor miRs (TSmiRs) in response to the HT and HIIT. RESULTS: In women with breast cancer versus healthy controls, the expression of some oncomiRs was significantly increased - miR-21 (P<0.001), miR-155 (P=0.001), miR-221 (P=0.008), miR-27a (P<0.001), and miR-10b (P=0.007) - and that of some TSmiRs was significantly decreased - miR-206 (P=0.048), miR-145 (P=0.011), miR-143 (P=0.008), miR-9 (P=0.020), and let-7a (P=0.005). Moreover, HT considerably downregulated oncomiRs and upregulated TSmiRs. HIIT for 12weeks with HT significantly decreased the expression of the oncomiRs and significantly increased that of the TSmiRs as compared with HT alone. CONCLUSIONS: HITT could amplify the decrease and/or increase in expression of miRs associated with HT in women with breast cancer. A prospective trial could determine whether the use of circulating miRs for monitoring treatment can be useful in therapy decisions. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (No.: IRCT201202289171N1).