Background: Neoadjuvant (chemo-)radiation has proven to improve local control compared to surgery alone, but this improvement did not translate into better overall or disease-specific survival. The addition of oxaliplatin to fluoropyrimidine-based neoadjuvant chemoradiotherapy holds the potential of positively affecting survival in this context since it has been proven effective in the palliative and adjuvant setting of colorectal cancer. Thus, the objective of this systematic review is to assess the efficacy, safety, and quality of life resulting from adding a platinum derivative to neoadjuvant single-agent fluoropyrimidine-based chemoradiotherapy in patients with Union for International Cancer Control stage II and III rectal cancer. Methods: MEDLINE, Web of Science, and Cochrane Central Register of Controlled Trials will be systematically searched to identify all randomized controlled trials comparing single-agent fluoropyrimidine-based chemoradiotherapy to combined neoadjuvant therapy including a platinum derivative. Predefined data on trial design, quality, patient characteristics, and endpoints will be extracted. Quality of included trials will be assessed according to the Cochrane Risk of Bias Tool, and the GRADE recommendations will be applied to judge the quality of the resulting evidence. The main outcome parameter will be survival, but also treatment toxicity, perioperative morbidity, and quality of life will be assessed. Discussion: The findings of this systematic review and meta-analysis will provide novel insights into the efficacy and safety of combined neoadjuvant chemoradiotherapy including a platinum derivative and may form a basis for future clinical decision-making, guideline evaluation, and research prioritization. Systematic review registration: PROSPERO CRD42017073064