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Background The Support, Health Information, Nutrition, and Exercise (SHINE) trial recently showed that a telephone adaptation of the Diabetes Prevention Program (DPP) lifestyle intervention was effective in reducing weight among patients with metabolic syndrome. The aim of this study is to determine whether a conference call (CC) adaptation was cost effective relative to an individual call (IC) adaptation of the DPP lifestyle intervention in the primary care setting. Methods We performed a stochastic cost-effectiveness analysis alongside a clinical trial comparing two telephone adaptations of the DPP lifestyle intervention. The primary outcomes were incremental cost-effectiveness ratios estimated for weight loss, body mass index (BMI), waist circumference, and quality-adjusted life years (QALYs). Costs were estimated from the perspective of society and included direct medical costs, indirect costs, and intervention costs. Results After one year, participants receiving the CC intervention accumulated fewer costs ($2,831 vs. $2,933) than the IC group, lost more weight (6.2 kg vs. 5.1 kg), had greater reduction in BMI (2.1 vs. 1.9), and had greater reduction in waist circumference (6.5 cm vs. 5.9 cm). However, participants in the CC group had fewer QALYs than those in the IC group (0.635 vs. 0.646). The incremental cost-effectiveness ratio for CC vs. IC was $9,250/QALY, with a 48% probability of being cost-effective at a willingness-to-pay of $100,000/QALY. Conclusions CC delivery of the DPP was cost effective relative to IC delivery in the first year in terms of cost per clinical measure (weight lost, BMI, and waist circumference) but not in terms of cost per QALY, most likely because of the short time horizon.