BACKGROUND: Altered subchondral bone mineral density (BMD) may be a possible contributor to osteoarthritis (OA) pain. We evaluated the relation of compartment-specific proximal tibial BMD, at varying depths beneath the subchondral surface, to knee pain. METHODS: Multicenter Osteoarthritis (MOST) study participants with knee CTs were included. A 3D imaging tool measuring BMD in relation to depth from the subchondral surface was used to assess proximal tibial subchondral BMD at depths of 0-2.5, 2.5-5.0, and 5-10 mm. Knee pain in the past 30 days was scored on a numeric rating scale (range 0-100), dichotomized at 40/100 to define presence of at least moderate pain. We cross-sectionally evaluated the relation of subchondral BMD to presence of knee pain using binomial regression with generalized estimating equations (to account for correlations between two knees per individual) for each compartment and depth in separate models, and adjusted for age, sex, and body mass index (BMI). RESULTS: We included 2082 participants (mean age: 61 years, 56.5% female, mean BMI: 29 kg/m CONCLUSION: Lower subchondral proximal tibial BMD measures were associated with prevalence of moderate knee pain in individuals with or at risk for knee OA, without differences by depth or compartment. These findings suggest bone remodeling responses throughout subchondral bone contribute to the knee pain experience.