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Background: Joint Injury is a major risk factor for osteoarthritis (OA) and an opportunity to prospectively examine its early processes. We investigated whether predefined baseline factors including demographic, clinical factors and protein analytes in knee synovial fluid (sf/SF) and in plasma/serum were associated with clinically relevant outcomes at two years after knee injury. Methods: This was a longitudinal cohort study (REC10/H0805/39;NCT02667756) with 150 individuals aged 16-50 recruited within 8 weeks of a clinically significant acute knee injury (effusion and structural injury on MRI), which was typically being treated surgically. Twelve SF and four plasma/serum biomarkers were measured by immunoassay as the exposures of interest. Primary outcome was “Knee Injury and Osteoarthritis Outcome Score” (KOOS)4. X-ray/3T-MRI knees were taken at baseline and two years. Linear and logistic regression models adjusting for predefined covariates assessed associations with 2year KOOS4 and secondary endpoints including new symptomatic (regular knee symptoms), tibio-femoral radiographic OA (TFROA, Kellgren Lawrence Grade 2 or more on an X-ray) respectively. Findings: Baseline KOOS4, medium/large knee effusion and moderate/severe SF blood staining and their interaction significantly predicted 2year KOOS4 (Coeff. -20·5 [95% confidence interval -34·8, -6·18]. Of the predefined markers, only sfMCP-1 and sfIL-6 -showed independent associations with 2year KOOS4 (-0.015[0.027,-0.004] and -0.0005[-0.0009,-0.0001] per change in 1 pg/ml units respectively), jointly with the interaction of effusion and blood staining accounting for 39% of outcome variability. New TFROA at two years was associated with baseline meniscal tear (OR5·7[1·25,25·92]). 13/22(59·1%) with new TFROA had no NHANES frequent knee symptoms. Only 3month medium/large effusion was associated with new symptomatic TFROA at two years (OR14·0[1·86,105·27]). No sf/blood markers were associated with predefined structural/symptomatic outcomes. Interpretation: Effusion-haemarthrosis was strongly associated with symptomatic outcomes after acute knee injury. The SF molecular protein response to acute knee injury (best represented by MCP-1 and IL-6) was independently associated with symptomatic but not with structural outcomes, with the biomarkers overall playing a minor role relative to clinical predictors. The relationship between symptoms and structure after acute knee injury and their apparent dissociation early in this process needs to be better understood to make clinical progress.