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In Mexico, 15% of haemophilia A ( HA) patients develop inhibitory alloantibodies in response to replacement therapy with factor VIII ( FVIII), requiring bypass therapy such as activated prothrombin complex concentrate ( APCC). Because bypass therapy has not been broadly available in Mexico even in recent years, this study aimed to evaluate the thrombin generation assay ( TGA) in assessing the response to FVIII or APCC treatment in patients with severe HA positive to inhibitors. We studied 189 patients with severe HA. Clinical severity was verified by one-stage APTT-based clotting assay. Inhibitors to FVIII were investigated by the Nijmegen-Bethesda (N-B) method, and type of inhibition was assessed through serial plasma dilutions. Thrombin generation was measured with the calibrated automated thrombogram in inhibitor-positive plasmas previously spiked and incubated with FVIII or APCC. Data were analysed using anova, Student or Fisher's exact tests. We detected 47 (24.9%) subjects with high-titre (5-1700 N-B U mL−1) and 25 (13.2%) subjects with low-titre inhibitor antibodies (0.6-4.7 N-B U mL−1). We found an association between kinetic behaviour and clinical response to FVIII ( P = 0.0049) or vs. FVIII response evaluated with TGA ( P = 0.0007). Global concordance between clinical and in vitro response was 70%. By evaluating the capacity of thrombin formation in a plasma sample, TGA predicts the response to FVIII or APCC therapy and allows individual optimization of resources in patients with severe HA and high-titre inhibitors. The inhibition pattern of the antibodies to FVIII:C correlated with the TGA parameters and showed an association with the clinical response to FVIII. [ABSTRACT FROM AUTHOR]