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Substantial deficits in the care of depression make the provision of new evidence-based care models a matter of increasing importance. So far, disease management programs (DMPs) have not been systematically assessed.This study was a systematic review and meta-analysis of randomized controlled trials investigating the effectiveness of DMP for depression as compared with usual primary care.Criteria for study selection were depression as main diagnosis in adults, the intervention DMP (evidence-based guidelines, patient/provider education, collaborative care, reminder systems, and monitoring), and trial quality A/B (Cochrane Collaboration guidelines) rated by 2 observers. Measurement instruments had to be published in peer-reviewed journals and filled out by the participants, their relations, or independent raters. Meta-analyses were conducted by using dichotomous outcomes within forest plots. Tests of heterogeneity, sensitivity analyses, and funnel plots were performed. Economic evaluations were descriptively summarized.DMP had a significant effect on depression severity, with a relative risk of 0.75 (95% confidence interval 0.70–0.81) in a homogeneous dataset of 10 high-quality trials. It was robust in all sensitivity analyses (evidence level 1A). Funnel plot symmetry indicated a low probability of publication bias. Patient satisfaction and adherence to the treatment regimen improved significantly, but only in heterogeneous models. The costs per quality adjusted life year ranged between $9,051 and $49,500.DMP significantly enhance the quality of care for depression. Costs are within the range of other widely accepted public health improvements. Future research should focus on the effect of long-term interventions, and the compatibility with health care systems other than managed-care driven ones.