Objective: Although recent trial results of anti-CD3 therapy are promising, there have been conflicting results of various immunotherapeutic agents used in patients with type 1 diabetes. We conducted a systematic review and meta-analysis to determine the efficacy of nonantigen-based immunotherapeutic approaches for preservation of beta-cell function in patients with type 1 diabetes. Methods: We searched MEDLINE, EMBASE, Cochrane CENTRAL, reference lists, and content expert files up to September 2006. Eligible studies were randomized controlled trials (RCTs) of antiproliferative agents (methotrexate, azathioprine), monoclonal antibodies (CD3, CD4), T-cell inhibitors (cyclosporin) and other immunotherapeutic agents (photopheresis, linomide, fusidin, buffy coat, intravenous immunoglobulin, BCG, nicotinamide) in patients with newly diagnosed type 1 diabetes followed for ≥ 6 months. Pairs of reviewers working independently and with adequate reliability assessed the trials' methodological quality, collected data, and conducted random-effects meta-analyses on measures of preservation of beta-cell function (e.g. C-peptide secretion, insulin independence). Results: Of the 299 potentially relevant articles identified after an initial search, 20 trials met selection criteria. Meta-analysis of 20 trials (n = 1187 patients) found a small to moderate improvement in beta-cell function with immunotherapy [vs. placebo, effect size 0.37, 95% confidence interval (CI) 0.14-0.6] but there was moderate inconsistency in results across trials (I2 65%, 95% CI 39-77%). Subgroup analysis suggested a greater effect of cyclosporin and antiproliferative agents on beta-cell function when used for ≥ 6 months (pooled effect size 0.77 vs. -0.11, respectively; P interaction = 0.002). Conclusions: Long-term immunotherapy may preserve beta-cell function in newly diagnosed patients with type 1 diabetes. Patients and clinicians must await the conduct of rigorous trials reporting on diabetes resolution, adverse events, and other patient-important outcomes. © 2008 Mayo Foundation.