BACKGROUND Increased synovial fibrinolytic activity (detected by increases in synovial D-Dimer concentrations) has been observed in different joint diseases in humans and adult horses, presumably in order to minimize fibrin deposition within the joint and thus avoid its detrimental effects. OBJECTIVE To investigate fibrinolytic pathway activation in joint sepsis in foals by measuring synovial D-Dimer concentrations. METHODS Eighteen septic foals with septic joints, 9 septic foals without septic joints, 9 systemically healthy foals with septic joint, and 3 controls are included. METHODS Prospective observational clinical study of foals admitted for septic arthritis. Synovial D-Dimer concentration and routine synovial fluid analysis were performed. Diagnosis of joint sepsis was made whenever synovial total nucleated cell count was >30,000 cells/μL, synovial total protein >4 g/dL, and neutrophil percentage of >80%, or synovial fluid culture resulted positive. Results were compared among groups by general lineal models. RESULTS Synovial D-Dimer concentration was significantly (P < .001) higher in the foals with septic joints compared with foals without joint disease (P < .001). CONCLUSIONS Septic joint disease is associated with a marked increase of synovial D-Dimer concentration (marked activation of the fibrinolytic activity) within the affected joint. Although further studies are needed, the measurement of synovial D-Dimer concentration may be considered a complementary diagnostic marker of septic joint disease.