Background: A growing body of evidence supports total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC), however the optimal regimen is yet to be determined and little is known on the quality-of-life (QOL) implications of these therapies. We report QOL data from the Averectal study, which assessed the efficacy and safety of neoadjuvant short course radiotherapy (SCR) plus chemo-immunotherapy for patients with LARC. Methods: Between July 2018 and October 2020, patients enrolled in the Averectal study were invited to fill the Functional Assessment of Cancer Therapy for colorectal cancer (FACT-C) throughout their treatment. We analyzed results at baseline (T0), at completion of SCR and chemo-immunotherapy (T1), and at last-follow up after total mesorectal excision (TME) (T2). Paired sample t-test was used to compare mean scores for individual patients. Results: 39 patients completed the FACT-C form at the specified points. Median follow-up duration was 25.7 months. Median age was 58 years (range 31-74 years), 25 (64.1%) were males, 1 (3.1%) had stage II disease and the rest (96.9%) had stage III. All patients received SCR then 6 cycles of mFOLFOX-6 plus avelumab followed by TME. The mean score differences of the FACT-C subscales at different time-points are summarized. At the end of TNT, the social (SWB), emotional (EWB), functional well-being (FWB) and colorectal cancer subscale (CCS) scores improved compared to baseline (not significant) but physical well-being score (PWB) worsened (21.05 vs 22.94 p=0.025). After TME, all scores except EWB and FWB improved compared to T1, and all scores improved compared to baseline. The CCS, which assesses colorectal cancer specific concerns, significantly improved between T0 and T2 (19 vs 21.06, p=0.003). Overall, trial outcome index (TOI), reflecting functional status, improved after TME compared to baseline. Conclusions: Adopting neoadjuvant chemo-immuno-radiotherapy followed by TME for LARC does not result in QOL deterioration compared to baseline, and can improve colorectal cancer specific concerns. Clinical trial information: NCT03503630.