More tightly coordinated response was revealed at the protein level in the tolerant varieties by proteomic analysis. Carbohydrate metabolism, redox homeostasis and protein transport were found activated in the tolerant varieties in functional enrichment analysis; while photosynthesis was suppressed. However, the networks of protein-protein interaction between more drought tolerant lines were richer and well connected. In the interaction networks of proteins, these two drought tolerant lines had key hub proteins which play pivotal roles in effective signal transduction. The results systematically presented the complex regulatory network basis of drought resistance in rice, and offered novel molecular targets for screening drought tolerance in rice.