BACKGROUND. The extent of medial meniscal extrusion (MME) that is associated with structural and symptomatic progression of knee osteoarthritis has not been defined yet. OBJECTIVE. The purpose of our study was to investigate MRI-based thresholds of MME that are associated with structural progression of knee degenerative disease and symptoms over a period of 4 years. METHODS. We studied 328 knees of 235 participants that were randomly selected from the Osteoarthritis Initiative cohort. MME was quantified on coronal sections of intermediate-weighted MRI sequences obtained at 3 T. Knee pain and cartilage abnormalities were measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale and the cartilage whole-organ MRI score (WORMS). General estimating equations with logistic regression models were used to correlate baseline MME and changes in pain (WOMAC) and cartilage damage (WORMS). ROC analyses were performed to determine the area under the ROC curve (AUROC). Individual thresholds were determined by maximizing the product of sensitivity and specificity. RESULTS. The AUROC for predicting progression of knee pain, medial compartment cartilage damage, and medial tibial cartilage damage were 0.71, 0.70, and 0.72, respectively, and the individual thresholds for MME were 2.5, 2.7, and 2.8 mm. A single threshold of 2.5 mm was determined by maximizing the mean of the product of sensitivity and specificity of the three outcome variables (knee pain progression, medial compartmental cartilage damage progression, and medial tibial cartilage damage progression). CONCLUSION. MME was associated with knee pain and cartilage damage progression over 4 years. A single threshold of 2.5 mm was found to be the most useful threshold for predicting knee pain, medial compartment cartilage damage progression, and tibial cartilage damage progression over 4 years. CLINICAL IMPACT. This threshold could be used to standardize the diagnostic criterion of extrusion and to better characterize the risk for subsequent structural and symptomatic progression of knee osteoarthritis.