A new process for ion exchange coupled crystallization is introduced for the removal of calcium ions from dicyandiamide. The effects of different ion-exchange resins, temperature, reaction time, stirring rate, and treatment amount and resin dosage on the removal of calcium ions in dicyandiamide were studied. On this basis, the crystallization process of dicyandiamide was optimized by response surface methodology, together with respective investigations on the effects of cooling rate, stirring rate, seed grain size and seeding time on the removal of calcium ions in dicyandiamide. It was found that the removal efficiency of calcium ion could reach up to 98.12%, during the ion-exchange treatment, and the value increased then fell, with the rise of stirring rate and temperature; the efficiency would improve, with the accumulation of resin dosage; but it would diminish with the increase of treatment amount; and the value would first rise and then remain unchanged when the reaction time was extended. In addition, the best conditions for crystallization are also provided. When the cooling rate is at 0.3 °C/min, the stirring rate 300 rpm, the seed size 60 meshes, and the seeding time 30 minutes, seeds in uniform size with the content of Ca2+ pharmaceutically qualified would be obtained, under the optimum process conditions.