OBJECTIVE: The aim of this study is to assess the effects of a prehabilitation program (PREOPtimize), consisting of Nordic Walking and resistance training exercises plus health education among patients with breast cancer, who are receiving neoadjuvant therapy to enhance postoperative functionality of the affected arm. A secondary aim will be to compare the short-term effects of the intervention on other patient-reported outcome measures. METHODS: This will be an assessor-blind, randomized controlled trial with a parallel group design conducted at a tertiary hospital. A sample of 64 patients with breast cancer scheduled for surgery and undergoing neoadjuvant chemotherapy will be recruited for the trial and randomly allocated to either (1) a prehabilitation program consisting of 2 weekly sessions of 75 minutes of Nordic Walking, muscle strengthening exercises, and health education sessions conducted between the fourth month of treatment and surgery or (2) usual care. Patients in both groups will be assessed at baseline, before surgery, and at 1 and 3 months after surgery. Assessed outcomes include functionality of the affected arm (QuickDash), arm volume, range of motion, handgrip strength, pain, fatigue, functional capacity, physical activity levels, and health-related quality of life. Adherence to the intervention in the prehabilitation group and adverse events will also be recorded. IMPACT: Prehabilitation for patients affected by breast cancer is rarely implemented in clinical practice. The results obtained with the PREOPtimize trial could show that prehabilitation is a feasible intervention for patients with breast cancer receiving neoadjuvant therapy that might enhance postoperative recovery of upper arm function as well as improve overall physical performance and health-related quality of life.