Background: The treatment in patients with metastatic colorectal cancer (mCRC) have limited effectiveness and options. And research findings have revealed that combining anti-angiogenesis inhibitors with programmed death-1(PD-1) inhibitors can reverse the immunosuppressive tumor microenvironment and synergistically enhance the antitumor immune response. The goal of the study was to add more real-world data to prove the clinical efficacy and safety of this regimen. Methods: We conducted a Real-World observation study by comparison of the efficacy and safety of fruquintinib versus fruquintinib combined with PD-1 inhibitor in patients with mCRC who received treatment between June 2019 and October 2022 in our center. Results: A total of 106 patients with mCRC were observed to receive fruquintinib(F group) (n = 26, mean age = 63 years, female = 46.2%) or fruquintinib combined with PD-1 inhibitor (FP group)(n = 80, mean age = 62 years, female = 46.3%). 3.8% of patients achieved partial response (PR) in FP group and 47.5% had stable disease (SD). Of the F group, no patient had PR and SD was 50%. No difference was found for median progression-free survival(PFS) (F group 6.7 months vs. FP group 4.5 months, p = 0.271). Median overall survival(OS) was significantly prolonged with F group compared with FP group (18.7 months vs. 13.6 months, p = 0.008), which was mainly attributed to the disease course before the treatment of fruquintinib or fruquintinib combined with PD-1 inhibitor in the two groups (42.9 months vs. 31.8 months, p = 0.031). And univariate Cox regression analysis showed that clinical factors (Stage at first diagnosis, PD-L1 gene, number of organs with metastases, and operative treatment) were associated with OS in the FP group (p < 0.05), while only PD-L1 gene positive had significant difference in multivariate analysis (p = 0.024). In the F group, no factors had a significant impact on OS in Cox analysis. Further analysis on immune indices in the FP group indicated that total-MDSCs and PMN-MDSCs significantly decreased after treatment (p = 0.039), mainly resulting from the PR/SD subgroup (p = 0.019) rather than the PD subgroup (p = 1.000). Most adverse events occurred between these two groups were very similar, while any grade of myelosuppression, hepatic injury, abdominal pain, palmar-plantar erythrodysesthesia and hypothyroidism were more frequently observed in the FP group and≥grade 3 myelosuppression was more common. Conclusions: Among patients with metastatic CRC, fruquintinib combined with PD-1 inhibitor couldn't significantly prolong PFS and OS compared with only fruquintinib therapy, but could made a few patients partial response. Total/PMN-MDSCs may be an important indicator of the efficacy of the combined therapy. The combined treatment increased more side effects, yet showed an acceptable safety profile.