To determine the association of knee bone size, cartilage volume, and body mass index (BMI) at baseline with knee cartilage loss over 2 years in younger or middle-aged adults. A total of 324 subjects (mean age 45 yrs, range 26-61) were measured at baseline and about 2 years later. Knee cartilage volume and bone size were determined using T1-weighted fat-saturated magnetic resonance imaging. In multivariable analysis, baseline knee bone size was negatively associated with annual change in knee cartilage volume at medial and lateral tibial sites (ß = -0.62% to -0.47%/cm(2), all p < 0.001). The associations disappeared at medial tibial site after adjustment for baseline cartilage volume and became of borderline statistical significance at lateral tibial site after adjustment for both baseline cartilage volume and osteophytes (ß = -0.29, p = 0.059). Baseline knee cartilage volume was consistently and negatively associated with annual change in knee cartilage volume at all 3 medial tibial, lateral tibial, and patellar sites (ß = -4.41% to -1.37%/ml, all p < 0.001). Baseline BMI was negatively associated with an annual change in knee cartilage volume, but only in subjects within the upper tertile of baseline cartilage volume, even after adjusting for cartilage defects (ß = -0.16% to -0.34%/kg/m(2), all p < 0.05). Our study suggests that both higher baseline tibial bone area and knee cartilage volume (most likely due to cartilage swelling) are associated with greater knee cartilage loss over 2 years. A higher BMI was associated with greater knee cartilage loss only in subjects with higher baseline cartilage volume.