Background: Fruquintinib, an antiangiogenic tyrosine kinase inhibitor (TKI), has demonstrated its significant survival benefits in metastatic colorectal cancer (mCRC) patients in both China and global phase III trials (FRESCO and FRESCO-2), but data on patients' health-related quality of life (HRQoL) was rare. A previous study on HRQoL of mCRC patients receiving another antiangiogenic TKI or placebo showed a decreased pattern in the mean utility index (UI) score of EuroQol 5-dimension (EQ-5D). This study intended to evaluate the HRQoL of mCRC patients receiving fruquintinib in the real world and describe its real-world treatment outcomes and compliance. Methods: This is a multicenter prospective observational study of patients with mCRC who were treated with fruquintinib monotherapy. Patient demographics, disease characteristics, and treatment history were recorded at baseline (before fruquintinib administration). Dosage record, treatment outcome, and HRQoL, which was measured by EQ-5D-5L scale and then converted to UI score, were recorded in each cycle. The UI score was described in total patients. The changes of it from baseline at key point (first cycle of fruquintinib) and end point (last cycle of fruquintinib) between subgroups, including prior use of VEGF inhibitors, RAS mutation status, etc, were compared by T-test or Wilcoxon rank sum test. Median progression-free survival (mPFS) was calculated using Kaplan-Meier method. The medication compliance rate was summarized according to the dosage record. Results: Data of 70 patients from five centers between May 2021 and November 2022 were evaluated in this study. Fruquintinib was used in second line treatment in 15.7% cases (N = 11), and in third or later line in 84.3% cases (N = 59). The median UI scores of EQ-5D-5L were 0.89, 0.78 and 0.73 at baseline (N = 70), key point of follow-up (N = 62) and end point of follow-up (N = 23), respectively. There was no significant difference between subgroups in median UI score changes from baseline, such as whether VEGF inhibitors were used previously or not (at key point, -0.07 vs. -0.11, p = 0.82, at end point, -0.21 vs. -0.26, p = 0.27), and whether RAS mutation or not (at key point, -0.02 vs. -0.04, p = 0.79, at end point, -0.21 vs. –0.16, p = 0.62). The mPFS of the total population was 4.8 months (N = 69, 95%CI 3.5-6.2), numerically longer than mPFS in FRESCO and FRESCO-2 trials. The mean actual (actual doses per cycle/21 days) and prescribed daily doses were 4.46 mg and 4.65 mg for 21 out of 28 days per patient, respectively. The compliance rate (actual/prescribed) of fruquintinib was 95.91%. Conclusions: As with the previous study, fruquintinib showed a similar gradually declined trend in HRQoL, which may be associated with disease deterioration in heavily pretreated mCRC patients. Fruquintinib has prolonged mPFS with good compliance in clinical practice.