OBJECTIVE To summarize the evidence on effectiveness of translational diabetes prevention programs, based on promoting lifestyle change to prevent type 2 diabetes in real-world settings and to examine whether adherence to international guideline recommendations is associated with effectiveness. RESEARCH DESIGN AND METHODS Bibliographic databases were searched up to July 2012. Included studies had a follow-up of ≥12 months and outcomes comparing change in body composition, glycemic control, or progression to diabetes. Lifestyle interventions aimed to translate evidence from previous efficacy trials of diabetes prevention into real-world intervention programs. Data were combined using random-effects meta-analysis and meta-regression considering the relationship between intervention effectiveness and adherence to guidelines. RESULTS Twenty-five studies met the inclusion criteria. The primary meta-analysis included 22 studies (24 study groups) with outcome data for weight loss at 12 months. The pooled result of the direct pairwise meta-analysis shows that lifestyle interventions resulted in a mean weight loss of 2.12 kg (95% CI -2.61 to -1.63; I(2) = 91.4%). Adherence to guidelines was significantly associated with a greater weight loss (an increase of 0.3 kg per point increase on a 12-point guideline-adherence scale). CONCLUSIONS Evidence suggests that pragmatic diabetes prevention programs are effective. Effectiveness varies substantially between programs but can be improved by maximizing guideline adherence. However, more research is needed to establish optimal strategies for maximizing both cost-effectiveness and longer-term maintenance of weight loss and diabetes prevention effects.