Background Bone marrow lesions (BMLs) are a known risk factor for incident knee osteoarthritis (OA), and deep learning (DL) methods can assist in automated segmentation and risk prediction. Purpose To develop and validate a DL model for quantifying tibiofemoral BML volume on MRI scans in knees without radiographic OA and to assess the association between longitudinal BML changes and incident knee OA. Materials and Methods This retrospective study included knee MRI scans from the Osteoarthritis Initiative prospective cohort (February 2004-October 2015). The DL model, developed between August and October 2023, segmented the tibiofemoral joint into 10 subregions and measured BML volume in each subregion. Baseline and 4-year follow-up MRI scans were analyzed. Knees without OA at baseline were categorized into three groups based on 4-year BML volume changes: BML-free, BML regression, and BML progression. The risk of developing radiographic and symptomatic OA over 9 years was compared among these groups. Results Included were 3869 non-OA knees in 2430 participants (mean age, 59.5 years ± 9.0 [SD]; female-to-male ratio, 1.3:1). At 4-year follow-up, 2216 knees remained BML-free, 1106 showed an increase in BML volume, and 547 showed a decrease in BML volume. BML progression was associated with a higher risk of developing radiographic knee OA compared with remaining BML-free (hazard ratio [HR] = 3.0; < .001) or BML regression (HR = 2.0; < .001). Knees with BML progression also had a higher risk of developing symptomatic OA compared with BML-free knees (HR = 1.3; < .001). Larger volume changes in BML progression were associated with a higher risk of developing both radiographic OA (HR = 2.0; < .001) and symptomatic OA (HR = 1.7; < .001). In almost all subchondral plates, especially the medial femur and tibia, BML progression was associated with a higher risk of developing both radiographic and symptomatic OA compared with remaining BML-free. Conclusion Knees with BML progression, according to subregion and extent of volume changes, were associated with an increased risk of OA compared with BML-free knees and knees with BML regression, highlighting the potential utility of monitoring BML volume changes in evaluating interventions to prevent OA development. ClinicalTrials.gov Identifier: NCT00080171 © RSNA, 2024 See also the editorial by Said and Sakly in this issue.