Recurrent acute respiratory tract infections (ARTIs) affect a large population, yet the specific decisive factors are largely unknown. Here we study a population of 4407 children diagnosed with ARTI, comparing respiratory virome and serum cytokine profiles associated with multiple ARTIs and single ARTI during a six-year period. The relative abundance of Propionibacterium phages is significantly elevated in multiple ARTIs compared to single ARTI group. Serum levels of TIMP-1 and PDGF-BB are markedly increased in multiple ARTIs compared to single-ARTI and non-ARTI controls, making these two cytokines potential predictors for multiple ARTIs. The presence of Propionibacterium phages is associated with higher levels of TIMP-1 and PDGF-BB. Receiver operating characteristic (ROC) curve analyses show that the combination of TIMP-1, PDGF-BB and Propionibacterium phages could be a strong predictor for multiple ARTIs. These findings indicate that respiratory microbe homeostasis and specific cytokines are associated with the onset of multiple ARTIs over time.