A decrease in proteoglycan (Pg) content and disturbances in the collagen network have been reported in aging cartilage. This study aims to determine whether these changes are associated with proteolytic enzymes such as neutral metalloproteases. Eighty lateral tibial plateaus were collected from subjects after death. The age, topographical area, and lesion severity (macroscopic grading) of each specimen were noted and the effects of neutral metallo-Pg-degrading and collagenolytic enzymes on these specimens were compared. The specimens were divided into two age groups: 20-50 years (group 1) and greater than 50 years (group 2). They were selected from both weight bearing and non-weight bearing areas. In some cartilage tissues the superficial layer was separated from the deep zone. Our data for the two neutral metalloenzymes examined showed: no correlation between enzyme activity and age when the specimens were of the same grade and a statistically significant rise in the enzyme levels of the older specimens, which increased as the lesions progressed. Neutral metallo-Pg-degrading enzyme activity was higher in non-weight bearing areas than in weight bearing areas, and this reached a statistical difference in the older cartilage with advanced lesions. The Pg-degrading enzyme activity was raised in the superficial layers of damaged cartilage tissue. Our data suggest that neutral metalloproteases are closely associated with the appearance and progression of the changes seen in aging cartilage.