Background: Neoadjuvant chemoradiation therapy (CRT) is a standard of care treatment for locally advanced rectal cancer (LARC). A pathologic complete response (pCR) following CRT is an early indicator of treatment benefit and associated with excellent survival outcomes. As capecitabine replaces infusional 5-fluorouracil (5-FU) as the fluoropyrimidine of choice in routine care of LARC, on the back of clinical trial data demonstrating equivalence, it is important to confirm that efficacy is maintained in the real-world setting. Methods: We analysed data from a prospectively maintained colorectal cancer database at 3 Australian hospitals including patients diagnosed January 2009 to December 2018. Pathological response was determined as either complete or incomplete and compared for patients receiving 5FU or capecitabine. Results: 657 patients were analysed, 498 receiving infusional 5-FU and 159 capecitabine. Capecitabine use has markedly increased from approval in 2014, now being used in more than 80% of patients. Patient characteristics were similar by treatment, including age, tumour location and pre-treatment stage. pCR was reported in 22/159 (13.8%) of capecitabine treated patients and 118/380 (23.7%) that received 5-FU (p = < 0.01). More capecitabine-treated patients received post-operative oxaliplatin (44.2% vs 6.3%, p < 0.01). Two-year progression free survival was similar (84.9% vs 88.0%, p = 0.34). Conclusions: Capecitabine is now the dominantly used neoadjuvant chemotherapy in LARC. Capecitabine use was associated with a lower rate of pCR versus infusional 5FU, a difference not explained by examined patient or tumour characteristics. Poor treatment compliance with an oral therapy in the real-world setting is one possible explanation.