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Summary: Background: When used proactively, drug‐tolerant anti‐tumour necrosis factor (TNF) antibody assays provide early opportunity to suppress immunogenicity. Aim: To validate positivity thresholds of IDKmonitor drug‐tolerant anti‐infliximab and ‐adalimumab antibody assays. Methods: We applied positivity thresholds, defined by testing sera from 498 anti‐TNF naive healthy adults, from the Exeter Ten Thousand study to data from our therapeutic drug monitoring (TDM) service and Personalised Anti‐TNF Therapy in Crohn's disease (PANTS) cohort to explore associations with drug level and treatment outcomes. Results: The 80% one‐sided lower confidence interval of the 99th centile concentration for anti‐infliximab and –adalimumab antibodies were lower than the manufacturers threshold of 10 arbitrary units (AU)/mL; 9 and 6 AU/mL, respectively. Using these new thresholds in the TDM cohort, more adalimumab‐ than infliximab‐ (11.2% [814/7272] vs 3.1% [390/12 683] P < 0.0001) treated patients were reclassified as antibody‐positive. Adalimumab drug concentrations in this reclassified group (median 8.1, interquartile range [IQR] 5.5‐11.0 mg/L) were lower than those below the new threshold (<5AU/mL) (median 9.9, IQR 7.1‐13.0 mg/L; P < 0.0001), but higher than at the manufacturer's threshold (10‐29 AU/mL) (median 5.9 mg/L, IQR 3.5‐8.7; P < 0.0001). No difference in infliximab drug concentration was observed using the new or manufacturer's positivity threshold (P = 0.11). In the PANTS cohort, patients with anti‐adalimumab antibody concentrations at or above the new threshold were more likely to be in primary non‐response (25/68 [37%] vs. 64/332 [19%], P = 0.0035), and non‐remission at week 54 (51/62 [82%] vs. 168/279 [60%], P = 0.0011), than patients with anti‐drug antibody concentrations in the group below the new threshold (0‐5 AU/mL); this was not seen for anti‐infliximab antibodies. Conclusion: Laboratories should derive antibody positivity thresholds for assays they use. For adalimumab, low‐concentration anti‐drug antibodies were associated with lower drug levels and treatment failure. [ABSTRACT FROM AUTHOR]