Sensorineural hearing loss (SNHL) is an irreversible disorder that severely compromises quality of life. Accumulating evidence has suggested that the loss of synapses between the inner hair cells and the peripheral terminals of the auditory nerve fibers (IHC synapses) plays a fundamental role in SNHL. Therefore, the aim of this study was to elucidate the cause of IHC synapse loss induced by repeated exposure to noise. IHC synapses were visualized by immunostaining with primary antibodies to c-terminal binding protein 2 (CtBP2), glutamate receptor subunit A2 (GluA2) and myosin VIIa. In this study, we showed that this repeated-noise exposure causes the loss of IHC synapses and a decrease in the gene expression level of c-fos, which is an indicator of nerve responses to stimuli. Subcutaneously administration of mice with PLX3397 (290 mg/kg/day, colony stimulating factor-1 receptor inhibitor) starting 1-week before first noise exposure significantly prevented the noise-induced IHC synapse loss. In addition, intraperitoneally administration of mice with minocycline (50 mg/kg/day, microglia activation inhibitor) during noise exposure period significantly prevented the noise-induced IHC synapse loss. These data suggest that noise-induced activation of cochlear macrophages is involved in the loss of IHC synapses.