Acquired hemophilia A (AHA) is a serious bleeding disorder due to neutralizing autoantibodies against factor VIII (FVIII). Emicizumab mimics the activity of FVIIIa restoring thrombin generation. It was shown to protect patients with AHA from bleeding, but some patients experience clinically relevant breakthrough bleeding. Therefore, monitoring the efficacy of emicizumab might be useful, potentially through thrombin generation assay (TGA). The aims of this study were to assess (i) how TGA is related to emicizumab levels, residual FVIII activity, and antigen concentration of other coagulation factors, and (ii) whether it can predict breakthrough bleeding during emicizumab prophylaxis. We used samples from patients enrolled in the GTH-AHA-EMI study that prospectively assessed the risk of bleeding in AHA patients receiving emicizumab for 12 weeks. Calibrated automated thrombogram assay was used with minute amounts of tissue factor (TF-TGA) or factor XIa (FXIa-TGA) to initiate coagulation. We observed that FXIa-TGA peak thrombin generation increased with emicizumab levels and FVIII activity. Higher peak thrombin values were associated with lower rates of bleeding as indicated by incident rate ratios (IRR) below 1 (IRR=0.40; 95% confidence interval: 0.17-0.84; P<0.05). TF-TGA was less sensitive to emicizumab and FVIII activity and was not associated with bleeding rate. FIX, FX and FXI antigen levels were not related to bleeding. In conclusion, FXIa-TGA was related to emicizumab levels and residual FVIII activity and to rates of clinically relevant bleeding. FXIa-TGA could be a useful biomarker to indicate increased risk of bleeding in patients with AHA emicizumab prophylaxis.