In humans, partial-thickness cartilage lesions frequently result in premature osteoarthritis. While rabbits often are used as a model for partial-thickness cartilage lesions, the natural course of cartilage surrounding such a lesion is largely unknown. We developed a rabbit model of a chronic partial-thickness cartilage defect and asked whether these defects led to (1) deterioration of surrounding cartilage macroscopically and microscopically (increased Mankin score) and (2) disturbances in proteoglycan metabolism. In 55 rabbits, we created a 4-mm-diameter partial-thickness cartilage defect on one medial femoral condyle. The surrounding cartilage was characterized during the course of 26 weeks. Contralateral knees were sham-operated. In experimental knees, we found cartilage softening and fibrillation at 13 and 26 weeks. High Mankin scores observed at 1 week were partially restored at 13 weeks but worsened later and were most pronounced at 26 weeks. Mankin scores in the experimental groups were worse at 1 and 26 weeks when compared with the sham groups. Mankin scores at 26 weeks improved compared with 1 week in the sham groups. Disturbances in proteoglycan metabolism were less evident. In this rabbit model, a partial-thickness cartilage lesion resulted in early markers of degenerative changes resembling the human situation.