Host recognition and immune-mediated foreign body response to biomaterials can compromise the performance of implantedmedical devices. To identify key cell and cytokine targets, here we perform in-depth systems analysis of innate andadaptive immune system responses to implanted biomaterials in rodents and non-human primates. While macrophagesare indispensable to the fibrotic cascade, surprisingly neutrophils and complement are not. Macrophages, via CXCL13,lead to downstream B cell recruitment, which further potentiated fibrosis, as confirmed by B cell knockout and CXCL13neutralization. Interestingly, colony stimulating factor-1 receptor (CSF1R) is significantly increased following implantation ofmultiple biomaterial classes: ceramic, polymer and hydrogel. Its inhibition, like macrophage depletion, leads to complete loss offibrosis, but spares other macrophage functions such as wound healing, reactive oxygen species production and phagocytosis.Our results indicate that targeting CSF1R may allow for a more selective method of fibrosis inhibition, and improve biomaterialbiocompatibility without the need for broad immunosuppression.