OBJECTIVE: Although obesity is widely accepted as a risk factor for knee osteoarthritis, it is not clear whether individual components of body composition, such as the mass and distribution of muscle and fat, are associated with development of the disease. This study examined the effect of measures of body composition on the longitudinal change in tibial cartilage volume. METHODS: Body composition, assessed via dual x-ray absorptiometry, and tibial cartilage volume, assessed via magnetic resonance imaging, were measured in 86 healthy men and women who were mid-life in age. Change in tibial cartilage volume was assessed by imaging each knee 2 years after the baseline measurement and determining the difference from baseline in tibial cartilage volume. Correlations were determined between the muscle and fat mass of the arm, leg, and total body and the volume of the lateral- and medial-tibial cartilage, as well as the change in tibial cartilage volume over 2 years, after adjusting for confounders. RESULTS: There was a significant association between muscle mass and the medial-tibial cartilage volume, independent of age, sex, body mass index, tibial bone area, and level of physical activity. Although there was a positive association between muscle mass and the lateral-tibial cartilage volume, this did not persist after adjustment for confounders. Loss of muscle mass was associated with an increased loss of medial- and lateral-tibial cartilage over 2 years, after adjusting for confounders. No relationship was apparent between fat mass and either medial- or lateral-tibial cartilage volume, or between fat mass and change in either medial- or lateral-tibial cartilage volume over 2 years, after adjusting for confounders. CONCLUSION: Muscle mass is an independent predictor of medial-tibial cartilage volume in healthy people in mid-life and is associated with a reduction in the rate of loss of tibial cartilage. This suggests that increased muscle mass may be protective against the onset of osteoarthritis.