Abstract Purpose To compare the benefits and harms of anti–tumor necrosis factor (TNF)-α and anti-integrin agents as induction and maintenance therapy in adult patients with Crohn’s disease. Methods We searched MEDLINE and the Cochrane Central Register of Controlled Trials from inception through July 2015 for randomized clinical trials in patients with Crohn’s disease who reported response or remission with anti–TNF-α or anti-integrin agents administered as induction and/or maintenance therapy. Data on the study population, interventions, outcome measures, adverse events, and study methods were extracted independently by 2 authors. Findings Among 2503 citations identified, 23 met the eligibility criteria. Random-effects model meta-analyses and network meta-analyses were performed. No statistically significant difference was observed between anti–TNF-α and anti-integrin agents with respect to induction and maintenance of response (odds ratio OR = 1.20 95% CI, 0.73–1.96 from 14 trials and OR = 1.23 95% CI, 0.50–3.03 from 8 trials, respectively) or remission (OR = 1.13 95% CI, 0.72–1.76 from 17 trials and OR = 1.18 95% CI, 0.55–2.50 from 9 trials, respectively). No difference was observed in the indirect comparison of trials that reported results on the subgroup of anti–TNF-α naive patients. The proportions of patients with adverse events, infections, and treatment discontinuations were similar between the agents. Implications Our indirect treatment comparisons did not find a statistically significant difference between anti–TNF-α and anti-integrin agents for induction or maintenance therapy. In the absence of head-to-head comparisons, it remains unclear which patient is more likely to respond better to any of these agents.