OBJECTIVE: To observe the effect of glucosamine (GS) and chondroitin sulfate (CS) on histopathological, histochemical features of articular cartilage and on the aggrecan serum level in Hartley guinea pigs: a kind of primary OA animal model. METHODS: 120 female Hartley guinea pigs aged 2 months were randomly divided into 3 test groups and a control group, 30 animals for each group. The three test groups refer to GS group, CS group and combined group. GS group has been administrated with 1 g/kg bw GS, CS group administrated with 0.5 g/kg bw CS, combined group with 1 g/kg bw GS + 0.5 g/kg bw CS and a control group administrated with distilled water. The above four substances were treated via ad limbitum for a period of 5 months. Before dosing and after each monthly treatment during the five months, knee joints Cartilage specimens from 5 guinea pigs each group were examined through histopathological method (H. E stain) and histopathological method (Alcain Blue, PAS and Mallory stain), and the serum levels of aggrecan were detected synchronously. RESULTS: During the entire 5 months period, distinct pathological lesions appeared just after the first month in control group. And the distinct pathological lesions didn't appear until the third month ended in GS group. In CS group, moderate pathological lesions were observed in the fourth month, while there were almost no obviously pathological changes in combined group during the whole test period. The serum levels of aggrecan in all three test groups were all decreased slower after 4 months treatment than those in the control group, with a significant difference (P < 0.05). CONCLUSION: GS and CS can postpone and inhibit the pathological changes of articular cartilage, as well as serum aggrecan levels decrease in Hartley guinea pigs. The effect of GS and CS used in combination was stronger than individual GS and CS, showing a repair property.