<b><i>Background/Aims:</i></b> The efficacy of both Infliximab (IFX) and Adalimumab (ADA) can be reduced over time. The aim of this study was to analyze the incidence of loss of efficacy (LOE) of both IFX and ADA, and outline the influence of disease duration on its occurrence. <b><i>Methods:</i></b> Retrospective, multicenter, observational cohort study, with CD patients treated with anti-TNF therapy. LOE was defined as the need for steroids, occurrence of major abdominal surgery during treatment, dose increase, interval shortening or switching of the anti-TNF agent. Patients were allocated in three subgroups based on disease duration (DD): <24 months, between 24 and 60 months and >60 months. <b><i>Results:</i></b> 175 patients were included in the study (117 under IFX and 58 under ADA therapy). LOE occurred in 32% of patients with DD <24 months, in 33.3% with DD between 24 and 60 months and in 31.3% of subjects with DD over 60 months (p = 0.975). <b><i>Conclusions:</i></b> Disease duration (DD) did not influence LOE rates. These results suggest that in real-world observational practice, patients with early CD might have the same rates of LOE than patients with a disease prolonging for a longer duration.