Background: The FRESCO Study is a randomized, double-blind, phase III trial comparing fruquintinib + best supportive care (BSC), to placebo + BSC in the treatment of metastatic colorectal cancer (mCRC). This ad-hoc analysis aims to compare the quality-adjusted survival between the two arms using quality-adjusted time without symptoms or toxicity (Q-TWiST) methodology, and to investigate the Q-TWiST benefit of fruquintinib treatment among sub-groups. Methods: The survival time for each patient was divided into 3 portions: TOX (time with ≥ grade 3 toxicity before progression), TWiST (time without symptoms or ≥ grade 3 toxicity), and REL (time from progression or relapse until death or end of follow-up). Q-TWiST was calculated as the sum of the utility-weighted mean durations for each health state. Threshold analyses were conducted to understand Q-TWiST gains associated with utility weight and subgroup analyses were performed according to baseline clinical characteristics. Results: Of 416 patients randomized, 278 received fruquintinib treatment. Survival benefit was seen in Q-TWiST in patients in the fruquintinib arm when compared to those in the placebo arm (mean: 7.0 vs. 4.8 months, difference [95% CI]: 2.2[1.4, 3.0]) in the base case scenario (TOX = 0.5 and REL = 0.5). Threshold analyses suggested that Q-TWiST gains ranged from 16.7% to 39.9% and favored fruquintinib across all possible utility weight combinations. The differences in Q-TWiST favored patients in the fruquintinib arm across pre-specified subgroups. Patients benefited from fruquintinib treatment in terms of Q-TWiST gain regardless of prior targeted treatment (32.3% and 22.9% of those with and without prior targeted treatment, respectively). Conclusions: In mCRC patients who failed 2 lines of standard therapy, fruquintinib treatment resulted in more quality-adjusted survival benefits when compared to placebo arm. The benefits seen may have been achieved by good disease control and safety profile. Both patients with and without prior targeted therapy can benefit from fruquintinib treatment.