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OBJECTIVE: It remains unclear whether malalignment of the knee is a cause of knee OA or a marker of disease progression. We investigated whether baseline malalignment of the knee predicts subsequent change in knee cartilage volume and chondral defects in subjects with and without radiographic knee osteoarthritis (OA). METHODS: A convenience sample of 315 male and female subjects (mean age 45 yrs, range 26-61) was followed up for a mean period of 2.4 years. Anatomic knee alignment was assessed on a standing anterior-posterior semiflexed view of the right knee and defined as the angle subtended by a line drawn through the midshaft of the femur with respect to one drawn through the midshaft of the tibia. T1-weighted fat saturation magnetic resonance imaging scans were performed on the same knee at baseline and followup for cartilage volume and chondral defects. RESULTS: Knee alignment was normally distributed in this sample with a mean of 178.2 degrees (SD 1.9 degrees). Fifty-five percent of subjects were < 178.5 degrees, while 14% were > 180 degrees. After adjustment for age, sex, body mass index, previous knee injury, and OA family history, neither category of alignment at baseline was associated with subsequent loss of lateral and medial tibial cartilage volume. Similarly, there was no association between malalignment and progression of chondral defects. The results remained the same when stratified by radiographic OA status. CONCLUSION: Our adequately powered study shows that baseline knee alignment is not associated with subsequent loss of cartilage volume or progression of chondral defects over 2 years. Further studies with a longterm followup are needed, but these results suggest malalignment is primarily a marker of disease progression.