© 2016, INRA and Springer-Verlag France.Biofortification is a strategy for overcoming human zinc (Zn) deficiency, especially in rural areas of developing countries. Actually, biofortification by foliar Zn application has been demonstrated at small scale, but not at large scale due to the absence of economic analysis. Therefore, here, we conducted the first cost-effectiveness analysis using the method of “disability-adjusted life year” measuring the health burden. We thus quantified the cost of agronomic biofortification of wheat with Zn in three major wheat-growing regions of China. Our results show that the current annual health burden due to human Zn deficiency, defined as numbers of disability-adjusted life years lost, is 0.21 million years for the region under single wheat plantation, 0.79 million years for the region under wheat-maize rotation, and 0.38 million years for the region under wheat-rice rotation. Comparing with traditional wheat diets in these three regions, the consumption of agronomically Zn-biofortified wheat diets could increase the daily Zn intakes of infants and children under 5 years of age. These increased daily Zn intakes consequently reduce the health burden due to human Zn deficiency in these regions by up to 56.6 %. According to cost-effectiveness analysis, the cost for saving one disability-adjusted life year in these regions ranges from US$ 226 to US$ 594 for foliar Zn application alone. The cost ranges from US$ 41 to US$ 108 when foliar Zn and pesticide applications are combined to reduce labor costs. This cost of US$ 41–108 under the combined application of foliar Zn plus pesticide is lower than the World Bank’s standard.