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Background Whether infliximab induces true mucosal transcriptomic reprogramming or merely attenuates surface inflammation in IBD remains unknown. Using paired pre- and post-treatment biopsies, we characterised the molecular consequences of infliximab treatment, contrasting transcriptomic rewiring between responders and non-responders.Methods Paired colonic and ileal biopsies from GSE16879 (n=60 matched pairs; CD=36, UC=24) were integrated with 555 IBD and control samples from three GEO cohorts (GSE75214, GSE179285, GSE36807) using ComBat batch correction. Unsupervised consensus clustering (k=3) of all 616 samples defined three molecular subtypes: Metabolic-Absorptive (C1), Hypoxia-Metabolic (C2), and Inflammatory-EMT (C3), onto which treatment biopsies were projected. A 47-gene Fibrosis Risk Score (FRS) and 13-cell-type Total Immune Burden Score (TIBS) were computed per sample. Paired differential expression used FDR-corrected paired t-tests in responders (n=27 pairs) and non-responders (n=33 pairs) separately.Results Infliximab induced fundamentally divergent transcriptomic responses by outcome. Responders exhibited 694 significantly differentially expressed genes (134 up, 560 down), including downregulation of MMP3 (log2FC= -2.09), MMP1 (-1.57), IDO1 (-1.54), S100A8 (-1.30), and CXCL1 (-1.19), reflecting coordinated suppression of matrix remodelling, immune activation, and epithelial stress. Non-responders showed only 37 differentially expressed genes, a 19-fold difference.Subtype transition analysis revealed complete biological reorganisation in responders: all 9 patients in the Inflammatory-EMT subtype (C3) pre-treatment transitioned to Hypoxia-Metabolic (C2) post-treatment, with zero patients entering C3 after therapy. In contrast, 17 of 24 non-responders in C3 remained in C3, indicating molecular entrenchment. FRS declined significantly in responders (-0.114 → -0.644; p<0.0001) but only partially in non-responders (p=0.017). TIBS declined in both groups, confirming partial immune attenuation even in the absence of transcriptomic reprogramming.Conclusions Infliximab response is defined by wholesale mucosal reprogramming: 694 paired DE genes, complete Inflammatory-EMT to Hypoxia-Metabolic subtype transition, and fibrotic score normalisation. Non-responders exhibit near-complete molecular stasis, 19-fold fewer DE genes and persistent C3 retention, indicating biological refractoriness rather than inadequate drug exposure. Primary non-response represents a fundamentally distinct biological state requiring alternative therapeutic targeting, not dose escalation. Molecular subtype transition may serve as an objective, mechanism-based endpoint for mucosal healing assessment in IBD.