To assess whether changes in knee cartilage MR-based T2 relaxation times are associated with weight loss in individuals with risk factors for knee osteoarthritis (OA) compared with controls with stable weight. One hundred twenty-seven individuals with risk factors for knee OA were studied: 62 subjects had a body mass index (BMI) decrease≥10% over 48 months and 65 controls had a BMI change <3%. Cartilage segmentation from five knee compartments at baseline and 48-month follow-up was performed, and T2 maps were generated. The association of change in T2 values over 48 months in the weight-loss group versus the control group was assessed using multiple linear regression models. Weight loss was associated with significantly smaller increases in cartilage T2 in the medial femoral condyle (P = 0.035) and overall medial compartment (P = 0.006) compared with the controls. In a subgroup analysis comparing weight-loss subjects who were obese (BMI≥30 kg/m(2) ) and overweight (BMI 25-30 kg/m(2) ) at baseline, obesity was associated with smaller increases in cartilage T2 values in the medial femoral condyle (P = 0.022), lateral femoral condyle (P = 0.015), patella (P = 0.002), and globally across all compartments (P = 0.002). A decrease in BMI of ≥ 10% was associated with a slower progression of T2 values in individuals with risk factors for OA, suggesting a beneficial impact of weight loss on cartilage matrix degeneration.