Abstract: Objective To analyze the pathological change after periocular injection of triamcinolone and hyaluronidase in guinea pigs. Methods Twenty guinea pigs of clean grade were used in this study. The animals were randomly divided into 4 groups (n=5 each). The right eye was used as intervention side, while the left eye was used as control side. Group A received periocular injection of saline water 0.2 mL at right eyes, Group B received periocular injection of triamcinolone 2 mg (0.2 mL), Group C received periocular injection of hyaluronidase 80 IU (0.2 mL), Group D received periocular injection of triamcinolone 2 mg (0.1 mL)+hyaluronidase 80 IU (0.1 mL). The injection was performed once a week for totally 4 times. One animal from each group was sacrificed at day 3, 7, 14, 28 and 35 after the first injection. The specimens of periocular tissue were obtained for microscopic examination and transmission electron microscopic examination to observe the pathological changes. The expressions of transforming growth factor-β₁(TGF-β₁) in the granulomas were detected by immunohistochemistry stain method. Results Compared with the control side, group A presented no obvious change. Group C presented looser intercellular space than the control group. Foreign-body granulomas was seen in 2^nd-5^th pathological section of group B and in the third and fifth pathological sections of group D. The size of the granulomas was smaller and the density of fibroblast was lower in group D than those in group B. The immunohistochemistry stain of TGF-β₁ showed strong positive reaction in group B, while weakly positive reaction in group D. The positive staining cells in group D were fewer than those in group B, and the difference was statistically significant (P<0.05). Most of the fibroblasts in group B presented as pyknic type with oval nucleus, amounts of cytoplasm and cell organs under electronCM(155.3mmmicroscope. Comparatively, the fibroblasts in group C and D remain inactive with spindle nucleus, less cytoplasm and cell organs. Conclusion Repeated periocular injection of triamcinolone may cause the formation of foreign-body granulomas around the injection site, leading to fibrosis and adhesion at later period. The injection combined with hyaluronidase can enhance the diffusion and absorption of triamcinolone, relieving the possible fibrosis.