OBJECTIVES: Biosimilars are of growing regulatory and commercial importance, yet there is uncertainty about their safety and efficacy relative to their reference products. We summarized the evidence comparing biosimilar and reference tumor necrosis factor-alpha (TNF-α) inhibitors.  METHODS: We searched PubMed, EMBASE, Cochrane Collaboration Clinical Trials, and LILACS through September 15, 2015 for English-language trials and observational studies comparing the safety, efficacy, or pharmacokinetic profiles of biosimilar and reference TNF-α inhibitors. No restrictions were applied regarding study population, size, or design. Two reviewers assessed titles and abstracts and a third resolved discordances. A single reviewer completed the full text review and data extraction. We narratively synthesized the included studies. Strength of trial evidence was assessed using the Cochrane Collaboration instrument. Public registries of clinical trials were searched for unpublished trials. Our systematic review registration number on PROSPERO is #CRD42015025262. RESULTS: Of 3,365 publications identified, 15 were included: 8 randomized controlled trials (RCTs), 4 abstracts describing trial extensions, 2 retrospective case series and 1 cross-sectional study. Of the RCTs, two Phase 1 crossover trials were in healthy volunteers, one Phase 1 parallel-group study was in patients with ankylosing spondylitis, one Phase 1 parallel-group study was in patients with rheumatoid arthritis (RA), and four Phase 3 studies were in patients with RA. In the Phase 1 trials, biosimilars and reference biologics were equivalent in relevant pharmacokinetic parameters. In Phase 3 trials, treatment-emergent adverse events and serious adverse events were comparable across treatment arms. For all Phase 3 trials, patients receiving biosimilars and reference biologics showed similar American College of Rheumatology Remission Criteria (ACR20) responses. The risk of bias was generally low for all trials; incomplete follow-up was the most common bias. CONCLUSIONS: The existing published studies support the biosimilarity and interchangeability of these products.