A system of nature reserves is a necessary component of an integrated conservation strategy. The basic problem in the design of a nature reserve system is to select the smallest number of sites from a region for some conservation objectives. There are 33 nature reserves intended for the conservation of Red-Crowned Crane (Grus japonensis), totalling 3.1 million ha. Other habitats of Red-Crowned Crane are facing severe problems due to economic development and other human activities. GIS, iterative methods and the integer programming approach were employed to design the nature reserve system for Red-Crowned Crane, with conservation goals to protect 70 and 60% areas of highly and moderately suitable wetlands, respectively. The results indicated the need to designate six new nature reserves in Wulagai marsh, Duluhe River, Tumen River, Rizhao, Gaoyou Lake and Hongze Lake, and showed a protection zone in Songnen Plain (between Heilongjiang Province and Jilin Province) and three clusters of nature reserves in Sanjing Plain, which, will be used as reference for the designation of new nature reserves, or enlargement and adjustment of existing nature reserves. The iterative method and integer programming approaches were feasible for design of nature reserve system.