Objective To investigate the relationship between serum adiponectin level and risk of colorectal cancer, and to explore the effect of recombinant adiponectin on the proliferation and apoptosis of colorectal cancer HCT116 cells. Methods Serum adiponectin levels in patients with colorectal cancer and healthy controls were dectected by ELISA. With the level of adiponectin as a risk factor, ROC curve was acquired using SPSS software. HCT116 cells were treated with recombinant adiponectin (2.5, 5, 10, 20 μg/mL). Then cell proliferation activity was detected by MTT assay. Cell cycle and apoptosis were detected by flow cytometry. The protein expressions of p21, NF-κBp65, phosphorylated NF-κBp65 (p-NF-κBp65), cyclin D1 and cleaved caspase 3 (c-caspase-3) were tested by Western blot analysis. Results The levels of serum adiponectin in the patients were significantly lower than those in the healthy controls. When the level of adiponectin was used as a risk factor, the area under ROC curve was 0.887 (95% CI: 0.807-0.966). Recombinant adiponectin inhibited the survival rate of HCT116 cells in a time- and dose-dependent manner. After the treatment with recombinant adiponectin, the percentage of HCT116 cells in G1/G0 phase increased and the expression of p21 was upregulated, while the expressions of p-NF-κBp65 and cyclin D1 were down-regulated. Meanwhile, the expression of c-caspase-3 increased and the percentage of apoptotic cells also increased. Conclusion The decreased level of serum adiponectin is closely related to the risk of colorectal cancer. Recombinant human adiponectin can inhibit the proliferation of colorectal cancer HCT116 cells, induce cell arrest at G1/G0 phase and promote apoptosis, which may be related to the down-regulation of NF-κB, cyclin D1, and activation of p21 and caspase-3.