Objective To evaluate the histocompatibility of small molecular hyaluronic acid combined with β-glucan, polylactic acid and hydroxyapatite. Methods Eighteen Wistar rats were randomly divided into three phases of experiments, with 6 rats in each phase. Four parts were divided on the back and divided into 4 groups according to different formulations of reagents. The control group was injected with 1.00 ml of small molecular hyaluronic acid, the dextran group was injected with 0.25 ml of small molecular hyaluronic acid+0.75 ml of β-glucan, the polylactic acid group was injected with 0.25 ml of small molecular hyaluronic acid+0.75 ml of polylactic acid, and the hydroxyapatite group was injected with 0.25 ml of small molecular hyaluronic acid+0.75 ml of hydroxyapatite. The rats were sacrificed after 7, 14 and 28 days of injection, and the tissues at the injection site were taken and made into sections. The immune response was observed after HE staining, and the expression level of interleukin 1 in the skin tissue of the third phase of the experimental rats was detected by Western blotting. Results In the 7 d experiment, the polylactic acid and hydroxyapatite groups showed a slight immune response. In the 14 d experiment, the immune response of each group showed an upward trend, and the immune response of each group subsided in the 28 d experiment. The results of immunoblotting showed that the expression of IL-1 in the injection site of the three groups was low in the 28 d experiment, and the difference was not statistically significant (P>0.05). Conclusion The combination of small-molecule hyaluronic acid with β-glucan, polylactic acid and hydroxyapatite has good histocompatibility.