OBJECTIVES: Obesity adjustments may have a substantial effect on models of long-term cost-effectiveness of intensive lifestyle intervention to prevent type 2 diabetes (T2DM). The objectives of this study were to: 1) design a long-term cost-effectiveness model to evaluate the use of lifestyle intervention to prevent progression from impaired glucose tolerance (IGT) to T2DM; and 2) to analyze the effect of obesity adjustments for mortality and costs on the model. METHODS: Markov models were developed based on the DPP results incorporating the states of normal glucose tolerance (NGT), IGT, T2DM and death. Transition probabilities were derived from DPP and current literature. A three-year intervention was assumed with outcomes of: 1) a three-year duration of effect; and 2) a lifetime duration of effect. A second set of models included an additional increased cost of illness for obese NGT subjects, and an increased mortality rate for obese T2DM subjects over the base-case. RESULTS: Lifestyle dominated placebo in all models tested. In the obesity-adjusted model, subjects had higher lifetime costs and shorter duration of life. The following incremental cost-effectiveness ratios were derived: 1) base-case model – three-year duration = -$16,064/LY; 2) base-case model – lifetime duration = -$19,496; 3) obesity-adjusted model – three-year duration = -$2,278/LY; and 4) obesity-adjusted model – lifetime duration = -$4,281/LY. A maximal acceptable cost of intervention per year for the three-year duration of effect that could be used to maintain lifestyle dominance was also established. The value for the obesity-adjusted model was approximately 45% of that found for the base-case model. CONCLUSION: Researchers examining the cost-effectiveness of intensive lifestyle intervention to prevent T2DM should be aware of the potential effect of obesity adjustments when developing models, in particular, the effects of obesity on mortality and costs for NGT subjects.