Prothrombotic and metabolic variables are decreased after obesity surgery, and fibrin clot lysis is increased. It is unknown how fibrinolytic variables are affected, and whether fibrinolytic and metabolic changes predict the enhanced clot lysis. Study aims were to determine fibrinolytic biomarkers before and 6 months after Roux-en-Y gastric bypass (RYGB) and to identify predictors of the RYGB-induced increase in clot lysis. Women (n = 42) and men (n = 18) with obesity underwent RYGB, and factor XIII (FXIII), thrombin activatable fibrinolysis inhibitor (TAFI), plasminogen and plasmin inhibitor (PI) were measured before and 6 months after surgery. Regression analyses identified determinants of the RYGB-induced increase in clot lysis among changes in fibrinogen and in fibrinolytic and metabolic variables. Results showed that after RYGB, FXIII, TAFI, plasminogen and PI were reduced (P < .0005). Reductions in PI (β = -0.59) and fibrinogen (β = -0.35), together with age (β = -0.22) and male sex (β = 0.22), predicted the enhanced clot lysis with the model explaining 56% (P < .0005). Predictors of the reduction in PI were reductions in cholesterol (β = 0.37) and glucose (β = 0.29), together with male sex (β = -0.28), whereas reductions in fibrinogen were predicted by lowering of interleukin-6 (IL-6) (β = 0.32). In conclusion, fibrinolytic variables were reduced 6 months after RYGB. Targeting PI and fibrinogen, by reducing metabolic variables such as glucose, cholesterol and IL-6, has a profibrinolytic effect in obesity.