Objective To describe the natural history of quantitatively measured knee effusion-synovitis and the longitudinal associations between effusion-synovitis and knee structural factors, including cartilage defects, cartilage volume, subchondral bone marrow lesions, and meniscal pathology, in older adults. Methods A total of 406 subjects (with a mean age of 63 years, 50% women) were randomly selected at baseline and followed up 2.7 years later. T2- or T1-weighted fat saturation magnetic resonance imaging was used to assess knee effusion-synovitis maximal area, cartilage defects, cartilage volume, bone marrow lesions, and meniscal pathology at baseline and follow-up. Multivariable generalized linear regression was performed to analyze the associations between the maximal area of effusion-synovitis and other joint structural factors after adjustment for age, sex, body mass index, tibial bone area, and/or radiographic osteoarthritis (OA). Results Over 2.7 years of follow-up, the size of effusion-synovitis increased in 29%, remained stable in 50%, and decreased in 22% of the participants. Baseline effusion-synovitis maximal area was significantly associated with changes in knee cartilage defects (β = 0.18 [95% confidence interval (95% CI)] 0.07, 0.29), bone marrow lesions (β = 0.17 [95% CI 0.05, 0.30]), and cartilage volume (β = -0.40 [95% CI -0.71, -0.09]) but not with change in meniscal pathology. In contrast, baseline structural measures were not associated with change or increase in effusion-synovitis maximal area. Conclusion Our findings indicate that knee effusion-synovitis is not static in older adults. It is predictive of, but not predicted by, other structural abnormalities, suggesting a potential role in early knee OA changes.