Background: Immune checkpoint inhibitors (ICIs) are highly effective in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC). However, the population of MSI-H/dMMR only accounts for 5% of mCRC. And most of the remaining microsatellite stable or proficient mismatch repair (MSS/pMMR) mCRC patients appeared not to benefit from mere immunotherapy. Fruquintinib, as the standard third-line regimen for mCRC, is an oral small-molecule anti-angiogenic tyrosine kinase inhibitor. Studies demonstrated that fruquintinib combined with programmed death receptor-1 (PD-1) inhibitors (FP) can reverse the immunosuppression and achieve promising efficacy. However, due to the lack of the research comparing the efficacy between fruquintinib monotherapy (FM) and FP, it remains unclear if FP can bring extra benefit. Methods: This is a retrospective cohort study conducted in the First Affiliated Hospital of Zhengzhou University. Patients (pts) with MSS/pMMR mCRC who had received at least the 2nd line treatment were eligible. Propensity score (PS) would be calculated to balance the baseline characteristics of two cohorts. Progression-Free survival (PFS) was set as the primary endpoint. The Kaplan–Meier method and Cox proportional hazard model was used to evaluate PFS and to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: From Apr 2020 to Jan 2023, 83 eligible pts in total were enrolled. According to the treatment received, 47 and 36 pts were respectively allocated into FP cohort and FM cohort. With a global median follow-up of 16.5 mo, the crude PFS was 6.8 (95% CI: 4.3-11.3) mo in FP cohort vs. 3.9 (3.1-4.7) mo in FM cohort. The HR of FP was 0.58 (95% CI: 0.34-0.98, FM as reference). Multivariate Cox regression showed that the adjusted HR was 0.49 (95% CI: 0.26-0.93), which was adjusted with sex, age greater than 65 yr, ECOG-PS, RAS mutation, BRAF mutation, location of lesion (left or right), surgery history, metastases (liver and lung), prior medication (bevacizumab and cetuximab), and current line (3 or later). With PS, we performed three statistical methods, namely inverse probability weighting, PS matching (the sample size was 37 vs. 29 after matching), and additional adjustment for propensity score with multivariate cox regression. The HR of FP were 0.49 (95% CI: 0.26-0.94), 0.40 (95% CI: 0.21-0.77), and 0.46 (95% CI: 0.24-0.90), respectively. Conclusions: Pts in FP cohort showed a significantly greater PFS than those in FM cohort. And with further analysis, FP indicated robustly lower HRs than FM. Our study suggests FP could provide additional benefits to pts with MSS/pMMR mCRC, and warrants further investigations in a large cohort.