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Introduction Upadacitinib (UPA) is an oral, selective, reversible janus kinase (JAK) 1 inhibitor approved for the treatment of moderately to severely active ulcerative colitis (UC). The impact of concomitant 5-aminosalicyclate acid (5-ASA) therapy on the efficacy and safety of UPA in patients with UC is unclear.Methods This post-hoc analysis compared outcomes with UPA and 5-ASA (UPA+5-ASA) versus UPA alone in patients with moderately to severely active UC enrolled in the phase 3 induction and maintenance trials (U-ACHIEVE [ NCT02819635], U-ACCOMPLISH [NCT03653026]). Only patients randomized to UPA for induction (45 mg QD [UPA45]) and maintenance (15 [UPA15] or 30 mg QD [UPA30]) therapy were included. Multivariable logistic regression analysis was used to evaluate the effect of concomitant 5-ASA on key primary and key secondary endpoints at weeks 8 (induction) and 52 (maintenance); odds ratios (OR) and 95% confidence intervals (CI) were calculated. The results were adjusted for baseline disease characteristics (Adapted Mayo score, disease extent, high-sensitivity C-reactive protein (hs-CRP), fecal calprotectin (FCP) concentration, corticosteroid use, sex, and prior biologic failure). Adverse events (AEs) were also assessed, with Incidence rate determined for pooled induction and exposure-adjusted event rate (events/100PYS) determined for maintenance.Results Of the 719 patients treated with UPA45 in the induction studies, 482 (67%) and 237 (33%) received UPA with and without 5-ASA, respectively. There were no differences between UPA+5-ASA versus UPA alone in achieving clinical remission at week 8 (OR [95% CI]: 0.96 [0.63-1.46] for UPA45) and week 52 (1.38 [0.62-3.07] for UPA15, 1.30 [0.54-3.11] for UPA30). Similarly, no differences were observed between UPA+5-ASA versus UPA alone in achieving the key secondary endpoints of clinical response (per Adapted Mayo score), mucosal healing, normalization of hs-CRP, normalization of FCP, and biochemical remission (normalization of both hs-CRP and FCP) at weeks 8 and 52. Incidences and exposure-adjusted event rates (events/100PYS) of AEs and AEs of special interest did not differ significantly between treatment groups.Conclusions Concomitant 5-ASA use did not impact the efficacy and safety of UPA induction and maintenance therapy in patients with moderately to severely active UC from phase 3 induction and maintenance studies.