Objectives. This study is undertaken to investigate the relation between osteopontin (OPN) and Wnt5a expression in the progression and pathogenesis of osteoarthritis (OA). Methods. 50 cartilage tissues from knee OA patients and normal controls were divided into four groups of severe, moderate, minor, and normal lesions based on the modified grading system of Mankin. Immunohistochemistry and real-time PCR were utilized to analyze the OPN and Wnt5a expression in articular cartilage. Besides, the relations between OPN and Wnt5a expression and the severity of OA were explored. Results. OPN and Wnt5a could be identified in four groups' tissues. Amongst the groups, the intercomparisons of OPN expression levels showed statistical differences (P < 0.01). Besides, the intercomparisons of Wnt5a expression degrees showed statistical differences (P < 0.05), except that between the minor and normal groups (P > 0.05). The scores of Mankin were demonstrated to relate to OPN expression (r = -0.847, P < 0.01) and Wnt5a expression in every group (r = -0.843, P < 0.01). Also, a positive correlation can be observed between the OPN and Wnt5a expression (r = 0.769, P < 0.01). Conclusion. In articular cartilage, the expressions of OPN and Wnt5a are positively related to progressive damage of knee OA joint. The correlation between Wnt5a and OPN might be important to the progression and pathogenesis of knee OA.