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Background Thalidomide-induced peripheral neuropathy (TiPN) often necessitates therapy withdrawal in Crohn’s disease (CD) management, and effective preventive or therapeutic measures remain lacking. Gut microbiota dysbiosis has been reported in peripheral neuropathy. Washed microbiota transplantation (WMT), the new method of fecal microbiota transplantation (FMT), represents an effective therapeutic approach for gut microbiota reconstruction. We aim to investigate the efficacy of WMT in ameliorating TiPN.Methods This multicenter retrospective study enrolled patients diagnosed with CD who received thalidomide therapy between January 2015 and February 2026. Participants were allocated to either the WMT group or the control group based on whether they underwent WMT treatment. The primary endpoint was the cumulative incidence of TiPN within one year. Secondary outcomes included the rate of drug discontinuation due to TiPN. The Kaplan-Meier method was used to plot survival curves, and the log-rank test was employed to compare differences between groups. Multivariate Cox regression analysis was performed to adjust for confounding factors and evaluate the independent protective effect of WMT. Subgroup analyses were conducted to verify the consistency of the effect.Results A total of 155 patients were enrolled, including 111 in the WMT group and 44 in the non-WMT group. Kaplan-Meier curves showed that the WMT group consistently exhibited higher PN-free survival rates than the non-WMT group (log-rank P < 0.001, IDDF2026-ABS-0521 Figure 1. Kaplan Meier curves for freedom from TiPN in the two patient groups). Multivariate Cox regression analysis identified WMT as an independent protective factor against PN (HR = 0.47, 95% CI: 0.25–0.87, P = 0.016, IDDF2026-ABS-0521 Figure 2. Forest plot from multivariable Cox regression analysis). The 1-year cumulative incidence of PN was significantly lower in the WMT group than in the non-WMT group (26.6% vs. 64.2%, P < 0.001), and the rate of PN-related treatment discontinuation was also significantly reduced (12.6% vs. 38.6%, P = 0.021). Subgroup analyses demonstrated consistent protective effects of WMT across patients stratified by sex, age, disease activity, and presence of perianal lesions (P interaction > 0.05, IDDF2026-ABS-0521 Figure 3. Forest plot of subgroup analysis effect of WMT on the risk of TiPN).Conclusions This study provides the first clinical evidence that WMT significantly mitigates TiPN in patients with CD and decreases treatment interruptions due to TiPN, addressing a critical unmet need in the management of drug-induced neurotoxicity.Abstract IDDF2026-ABS-0521 Figure 1Abstract IDDF2026-ABS-0521 Figure 2Abstract IDDF2026-ABS-0521 Figure 3