Objective To realize the characteristics of“zheng”differentiation-treatment for hand, foot and mouth disease (HFMD), a new methodology of syndrome differentiation for different stages of HFMD has been explored. Methods Total of 2 325 cases with HFMD were recorded by distributing them into exterior syndrome stage, interior syndrome stage, severe syndrome stage and recovered syndrome stage, respectively, and the main symptoms and subsidiary symptoms of different stages of HFMD have been observed. The major and minor pathogenesis of HFMD in different stages were obtained, and compared with the “2010 Guideline for the Diagnosis and Treatment of HFMD”. Results It was found that the major pathogenesis of exterior stage was deifned as“the invation of the wen-evil to the defender of the body with the collaterals got involved”, and the minor as“qi deifciency”;in interior stage,“the fury of Gan-Yang”was the main pathogenesis, and“qi in chaos and qi deifciency”was the minor;in severe syndrome stage,“the damage of heart, liver and lung”was the main pathogenesis, and“qi in chaos”was the minor;and the pathogenesis of recovered stage was“qi-yin deficiency”. Compared with the“2010 Guideline for the Diagnosis and Treatment of HFMD”, it showed that“the obstruction of the fei-pi qi by the mixture of shi-re evil”and“the mixture of shi-re”in vivo was quite dififcult to be explained in completely different context in the general situation; in the severe stage, the TCM clinical characteristics of syndrome differentiation might lose;in the early acute severe cases, the phenomenon that xin-yang and fei-qi almost ran out was dififcult to be observed, then, the line between the severe and the acute severe became vague. Conclusions The theory of syndrome differentiation by stages of HFMD was reasonable in the actual situation of clinical description on HFMD which was expected to be further tested and widely applied in the“zheng”differentiation-treatment of HFMD in the future.