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A notable proportion of patients with inflammatory bowel disease (IBD) are switched from infliximab (IFX) to adalimumab (ADL). We investigated if immunogenicity of IFX influenced immunogenicity and clinical outcomes of later ADL therapy.Single-center cohort study including all patients with IBD assessed for antibodies (Abs) against IFX or ADL.Anti-IFX Abs were evaluated in 187 patients treated with IFX as first line anti-TNF agent. Approximately, half (49%) were positive. Detected anti-IFX Abs had functional capacity as judged by a median IFX concentration below limit of detection (interquartile range, 0.0–0.0 μg/mL) versus 3.8 μg/mL (IQR, 1.3–7.9) in anti-IFX Ab-negative patients, P < 0.0001; but did not cross-react with ADL. Anti-ADL Abs were assessed in 57 ADL-treated patients. Twelve (21%) tested positive. Patients with previous anti-IFX Ab development were significantly more prone to develop anti-ADL Abs (33%) than those without (0%): odds ratio estimated 11, P = 0.04. The anti-ADL Abs were also functional because ADL was undetectable in all anti-ADL Ab-positive patients versus median 8.3 μg/mL (IQR 5.0–11.0) in anti-ADL-negative patients, P < 0.0001. The presence of anti-ADL Abs increased the risk of secondary ADL treatment failure with OR 28 (3–248), P < 0.001. ADL trough levels, irrespectively of anti-ADL Ab status, associated with efficacy of ADL maintenance therapy: AUCROC 0.77 (0.62–0.93), P < 0.01.Switchers with anti-IFX Abs are prone to develop de novo anti-ADL Abs, which may result in therapeutic failure. Assessment of ADL immunogenicity in anti-IFX Ab-positive switchers is required to ensure optimal interventions at inadequate treatment responses and to avoid inappropriate ADL intensification regimens.