Background: Trifluridine/tipiracil (FTD/TPI) is indicated and recommended for the treatment of previously treated metastatic colorectal cancer (mCRC). Previous evaluations used pooled clinical evidence from the Phase III (RECOURSE) and Phase II trials to model cost-effectiveness, but FTD/TPI specific utilities were not available and alternative data sources were used. The aim of this study was to utilize EQ-5D data from an ongoing Phase IIIb trial (PRECONNECT) within an updated cost-effectiveness model to validate health-related quality of life (HRQoL) outcomes for mCRC patients receiving FTD/TPI. Methods: EQ-5D-3L data from PRECONNECT trial were analyzed with UK utility tariff applied. Pre- and post-progression health state utilities were estimated using a linear mixed effects regression model. Indirect comparison versus regorafenib was based on evidence from the CORRECT trial. Utilities and UK costs (GBP, 2018) were then implemented into the existing economic model. Results: Mean pre-progression and post-progression utilities were 0.72 and 0.59, respectively, with discounted incremental quality adjusted life years gain of 2.1 months versus best supportive care (BSC) and 0.8 versus regorafenib. Use of FTD/TPI based on PRECONNECT data, as in the previous analysis, was associated with improved mean survival pre-progression (by 1.8 months) and post-progression (by 1.4 months) for the total OS gain of 3.2 months versus BSC. The mean OS gain versus regorafenib was 1.4 months. Updated cost-effectiveness analysis using PRECONNECT derived inputs showed that results remained broadly unchanged with a negligible increase in ICER from £51,589 to £51,792 (£51,101 in the probabilistic sensitivity analysis) when compared to BSC, while FTD/TPI remained dominant (more effective and less costly) versus regorafenib. Conclusions: New HRQoL data from the PRECONNECT study collected in a real-world setting validated previous HRQoL inputs used to model cost-effectiveness of FTD/TPI in previously treated metastatic colorectal cancer. Clinical trial information: NCT03306394