We studied whether contact stress estimates from knee magnetic resonance images (MRI) predict the development of incident symptomatic tibiofemoral osteoarthritis (OA) 15 months later in an at-risk cohort. This nested case-control study was conducted within a cohort of 3,026 adults, age 50 to79 years. Thirty cases with incident symptomatic tibiofemoral OA by their 15 month follow-up visit were randomly selected and matched with 30 control subjects. Symptomatic tibiofemoral OA was defined as daily knee pain/stiffness and Kellgren-Lawrence Grade !2 on weight bearing, fixed-flexion radiographs. Tibiofemoral geometry was segmented on baseline knee MRI, and contact stresses were estimated using discrete element analysis. Linear mixed models for repeated measures were used to examine the association between articular contact stress and case/control status. No significant intergroup differences were found for age, sex, BMI, weight, height, or limb alignment. However, the maximum articular contact stress was 0.54 AE 0.77 MPa (mean AE SD) higher in incident OA cases compared to that in control knees (p ¼ 0.0007). The interaction between case-control status and contact stress was significant above 3.20 MPa (p < 0.0001). The presence of differences in estimated contact stress 15 months prior to incidence suggests a biomechanical mechanism for symptomatic tibiofemoral OA and supports the ability to identify risk by subject-specific biomechanical modeling. Keywords: knee; osteoarthritis; biomechanics; epidemiology; risk In the U.S., about 9.3 million adults over age 60 have symptomatic knee osteoarthritis (OA), defined by radiographic findings and persistent pain or stiffness. Community-residing older adults are at especially high risk for disability.2,3 Pain is associated with disability due to functional limitations in mobility and self-care activities. 2,4 Research aimed at predicting symptomatic knee OA is important to clinical care and public health, because pain impacts participation in activities and prompts clinical presentation.Risk factors for knee OA include those that increase vulnerability (e.g., increased knee height or malalignment) and those that reduce recovery from excessive loading (e.g., excessive body mass index).5 However, not everyone with these factors develops symptoms, and no effective means of predicting which patients with these factors will develop incident disease currently exists. The ability to predict who will develop symptomatic knee OA would guide prognostication and possibly both prevention and therapy to reduce the incidence of symptomatic knee OA.Local mechanical stress at the articular surface leads to increased nitric oxide production and chondrocyte apoptosis. [6][7][8][9] This suggests that mechanical stress may be key in OA pathogenesis. Epidemiological factors for knee OA, such as obesity, increased knee height, and mechanical axis malalignment, are indirect global predictors of cartilage stress. They enable risk prediction on a population basis, but cannot account for loc...