Background <p>The use of immune-modifying biological agents has markedly changed the clinical course and the management of inflammatory bowel diseases (IBDs). Active post-marketing surveillance programs are essential for the early recognition of both expected and unexpected adverse events (AEs), providing a powerful tool for better defining the safety profiles of biologics in a real-world setting.</p> Methods <p>Patients diagnosed with IBDs and treated with biologic drugs at two gastroenterology units in Calabria, Italy, were monitored during the period from 2023 to 2024. AEs and drug switches or swaps were recorded. The primary objective was to assess the safety profile of biological therapies in real-world practice, as measured by the occurrence of AEs. Secondary objectives focused on assessing treatment effectiveness by monitoring rates of therapeutic ineffectiveness and rigorously analyzing necessary modifications to therapy (swaps/switches) in response to treatment failure.</p> Results <p>A total of 214 patients were enrolled, including 85 with Crohn’s disease (CD) and 120 with ulcerative colitis (UC). Among biologics, vedolizumab (VDZ) was the most prescribed drug (50.3%), followed by ustekinumab (UST, 33.6%). Among biosimilars, infliximab (IFX) was the most administered (70%), followed by adalimumab (ADA) (63.3%). 96 patients experienced AEs, though no serious adverse events (SAEs) were reported. The highest number of AEs was reported with VDZ (<i>n</i> = 31; 32.3%), followed by IFX (<i>n</i> = 22, 23.0%), ADA and UST (<i>n</i> = 17, 17.7%), and golimumab (GOL) (<i>n</i> = 7; 7.3%). The biological drugs associated with the fewest AEs were upadacitinib (UPA) and tofacitinib (TFC) (<i>n</i> = 1; 1.0%).</p> Conclusions <p>This study confirms the importance of pharmacovigilance in monitoring the safety of biologics in IBDs. The results offer useful insights into the actual use of monoclonals in gastroenterology and support more targeted prescribing.</p> Clinical trial number <p>Not applicable.</p>