To study on the proteome and to investigate the immune response mechanisms in P. skrjabini infection. Serum samples were randomly collected from patients with P. skrjabini infection and healthy individuals in Guizhou Province. ITRAQ (Isobaric Tags for Relative and Absolute Quantitation) assays were utilized for the analysis of protein catalogs in serum samples. Bioinformatics analysis on the differed proteins was performed. River crabs were sampled from the patients’ habitats, Paragonimus metacercariae were isolated for subsequent rat experimental infection. White blood cells and serum were collected at 42 days post-infection, changes in the expression of IL-4 were assessed. In result, a total of 50 proteins were identified. Typically, increased expression neutrophil defensin 3, protein S100-A9 (S100A9) and serum amyloid A-1 protein (SAA1) were found. S100A9 and SAA1 were involved in the main network but DEFA3 was not. The interaction networks were constituted with the core of Apolipoproteins family and the interactions with the fibrinogen and fibrinolytic system. Through subsequent experimental infections in rats, the expression of Th2 cytokines IL-4 remains unaltered. In conclusion, neutrophils may play a pivotal role in the elimination of parasites, whereas host Th2 cell immune response is suppressed in eliminating worms.