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Abstract Background The failure of disease-modifying osteoarthritis drugs (DMOADs) trials lies mainly in the heterogeneity of the disease, which calls for a more precise population with specific progression and outcomes. This study aimed to determine whether and which MRI-based structural phenotype of knee osteoarthritis (KOA) is associated with short-term structural progression and subsequent total knee replacement (TKR). Methods A longitudinal study was conducted among participants with baseline Kellgren-Lawrence grade (KLG) ≥ 2 from the Osteoarthritis Initiative (OAI). The structural phenotypes at baseline were defined as subchondral bone, meniscus/cartilage and inflammatory phenotypes according to the MRI Osteoarthritis Knee Score (MOAKS). The primary outcome was the progression of structural abnormalities within 24 months and multivariable logistic regressions were applied to evaluate the associations. The secondary outcome was the incidence of TKR during 108 months. Cox regressions and Kaplan–Meier survival curves were used for the analysis. Results A total of 733 participants with KOA were finally included in our study, with 493 (67.3%) having the three main structural phenotypes. For the primary outcome, the subchondral bone phenotype (OR [95% CI]:1.71 [1.02, 2.83], 1.52 [1.06, 2.18], 1.65 [1.11, 2.42], respectively) and the inflammatory phenotype (OR [95% CI]: 1.69 [1.05, 2.74], 1.82 [1.31, 2.52], 2.15 [1.48, 3.14], respectively) were both associated with the short-term progression of joint space narrowing, osteophytes and sclerosis in 24 months, whereas the meniscus/cartilage phenotype was only associated with the progression of osteophytes and sclerosis. For the secondary outcome, the subchondral bone phenotype (HR [95% CI]: 1.71 [1.06–2.78]) and inflammatory phenotype (HR [95%CI]: 2.00 [1.02–2.67]) were associated with shorter time to subsequent TKR, but not the meniscus/cartilage phenotype. Besides, the cumulative effect when the structural phenotype overlapped was confirmed in both outcomes. Conclusions The subchondral bone phenotype and inflammatory phenotype were associated with the progression of joint space narrowing, osteophytes and sclerosis in 24 months, along with subsequent TKR in 108 months. Besides, additive effects of overlapped phenotypes were further determined. These phenotypes could serve as valuable screening tools for future clinical trials and provide guidance for risk evaluation.