Spontaneous degeneration of the knee joint cartilage in male Hartley guinea pigs was studied by light microscopy in animals aged 3-18 months. Unilateral focal degeneration, characterized by chondrocyte death and proteoglycan loss with surface fibrillation, was observed on the medial tibial plateau in 2 of 5 guinea pigs that were 3 months old. The incidence and severity of the lesions increased with age, and by 12-18 months of age, all animals had moderate-to-severe degeneration of the medial tibial plateau, femoral condyle, and meniscus. Lesions were not present on the lateral aspect of the knee joint in any of the animals.