Factors driving the persistence of advanced therapies-defined as the duration from therapy initiation to discontinuation-in inflammatory bowel disease (IBD) remain unclear. This study aimed to evaluate the persistence of biologics and oral small molecules in a real-word IBD cohort and to identify influencing factors. Data from IBD patients starting advanced therapy at a tertiary referral centre after 2010 were retrospectively collected, including persistence and discontinuation reasons. Differences in persistence probability among therapies were analysed, and factors influencing persistence versus discontinuation due to failure were assessed by univariate and multivariate analyses. Among 274 included patients [median age 42.5 years; F/M 119/155; 146 with Crohn's disease (CD) and 128 with ulcerative colitis; median follow-up 38 months (IQR 14-75)], 141 (51.5%) remained persistent with first-line therapy, while 70 (26%) discontinued due to failure. No significant difference in persistence was observed among drugs (p = 0.11). Univariate analysis identified CD phenotype (p < 0.01), disease duration prior to therapy (p = 0.01), concomitant mesalamine or steroids (p < 0.01), and therapy optimisation (p < 0.01) as factors influencing persistence. Multivariate analysis confirmed CD phenotype as associated with higher persistence, while therapy optimisation was linked to increased discontinuation risk. CD was associated with better drug persistence, while therapy optimisation correlated with a higher discontinuation rate. Targeting deep healing and enhancing timely, precise optimisation strategies is essential for improving treatment outcomes.