Therapeutic drug monitoring of TNF-alpha inhibitors is crucial for evaluating patients with inflammatory diseases on a personalized level. It has been clinically observed that many patients receiving TNF-alpha inhibitors, with negative drug and anti-drug antibody results from bridging ELISA (bELISA), lose their drug response over time, despite dose optimization. Our aims were to develop innovative in-house competitive ELISAs (cELISAs) for the detection of neutralizing antibodies against infliximab and adalimumab and compare their results to reporter gene assay (RGA) and in-house bELISA. Furthermore, we aimed to evaluate patient anti-drug antibody results in regard to their clinical records and potential benefits of therapeutic drug monitoring with the novel cELISAs. Sera of patients treated with infliximab (n = 46) or adalimumab (n = 31), having undetectable drug levels, were tested with our in-house cELISA. Briefly, samples were incubated with a fixed amount of drug and the neutralizing capacity of the samples was determined. The cELISA results were compared to RGA and bELISA results using Spearman's correlation coefficient. Additionally, patient clinical data were evaluated in line with the results of cELISA, bELISA, and RGA using the Kaplan-Meier analysis and the Log Rank test. Both anti-infliximab and anti-adalimumab cELISAs showed very good correlation to RGA (r = 0.932, p < 0.0001 and r = 0.947, p < 0.0001, respectively). Furthermore, a positive result in anti-infliximab cELISA can predict treatment failure in 100% of patients with negative bELISA, while a positive result in anti-adalimumab cELISA can predict treatment failure in 80% of patients with negative bELISA. Taken together, we developed innovative cELISAs enabling quantification of functional and neutralizing anti-drug antibodies, comparable to RGA. The association between cELISA results and loss of drug response in patients identified clinically important anti-drug antibodies, as measured by cELISA.