Objective. The significance of asymptomatic knee cartilage defects in healthy individuals is not known. The aim of this study was to examine the association between cartilage defects in the knee and cartilage volume both cross-sectionally and longitudinally in healthy, middle-age adults. Methods. Eighty-six healthy men and women (mean SD age 53.8 8.8 years) underwent T1- weighted fat-suppressed magnetic resonance imaging of their dominant knees at baseline and at the 2-year followup visit. Knee cartilage volume was measured. Cartilage defects were scored according to a grading system (0a??4) and as present (a defect score of >2) or absent in the medial and lateral tibiofemoral compartments. Results. Cartilage defects in the medial and lateral tibiofemoral compartments were very common (in 61 and 43 of subjects, respectively). Those with cartilage defects had a 25 reduction in medial tibial cartilage volume, a 15 reduction in lateral tibial cartilage volume, and a 19 reduction in total femoral cartilage volume relative to those with no cartilage defects in cross-sectional analyses (all P <0.05). In the medial tibiofemoral compartment, the annual loss of tibial cartilage in those with cartilage defects was 2.5 (95 confidence interval [95 CI] 2.2 , 3.1 ) compared with an annual loss of tibial cartilage of 1.3 (95 CI 0.5 , 2.0 ) in those with no defects (P 0.028), independent of other known risk factors for osteoarthritis (OA). Conclusion. These data suggest that the presence of asymptomatic, nona??full-thickness medial tibiofemoral cartilage defects identifies healthy individuals most likely to lose knee cartilage in the absence of radiographic knee OA. Thus, interventions aimed at reducing or reversing cartilage defects may reduce the risk of subsequent knee OA.