BackgroundFOLFOX has emerged as a new treatment paradigm for locally advanced rectal cancer (LARC). However, whether FOLFOX, which replaces radiotherapy with chemotherapy, offers comprehensive clinical and economic advantages over conventional long-course chemoradiotherapy (LCCRT), especially in high-risk patients, remains unclear.MethodsWe conducted both within-trial and Markov model-based lifetime analyses to evaluate the short- and long-term economic and health outcomes of FOLFOX compared with LCCRT. Data were derived from the 3 and 10 year follow-up of the FOWARC trial (NCT01211210) in China and published data from the PROSPECT trial (NCT01515787) in the USA. Main outcomes included health utility, patient-reported outcomes of adverse events, costs, and quality-adjusted life years (QALYs). Costs were evaluated from the healthcare perspective in 2023 US dollars. Subgroup, scenario, and sensitivity analyses were performed.ResultsWithin-trial analysis showed that the FOLFOX group had an increasing utility trend, while LCCRT decreased. FOWARC found that LCCRT patients experienced more severe depression and social life impact compared with PROSPECT. Over 45.2 months, FOLFOX cost $3503 less and gained 0.18 more QALYs than LCCRT. Lifetime analysis estimated that FOLFOX gained 0.81 and 0.56 more QALYs, with cost savings of $12,018 and $87,643 compared with LCCRT in China and the USA, respectively. FOLFOX remained cost-effective in high-risk patients requiring supplementary radiotherapy, with LCCRT becoming preferable only when the proportion of these patients reached 64%.ConclusionsSelective radiotherapy avoidance with FOLFOX may be recommended for neoadjuvant treatment of LARC, even in high-risk patients. This substitution could save significant healthcare resources while improving QALYs globally.Trial Registration ClinicalTrials.gov NCT01211210, NCT01515787