Paclitaxel (Taxol) remains a mainstream treatment for many different types of cancers. However, paclitaxel-induced peripheral neuropathy (PIPN), characterized by debilitating nerve pain in distal limb(s), can force reducing the dose or even discontinuing the drug, leaving many cancer undertreated. Currently there is no effective treatment for this crippling pain syndrome. We recently reported that rats deficient in C3, a central component of the complement system, are protected in a model of PIPN. We showed that C3 is activated after paclitaxel treatment. C3 activation leads to the production of C3a, which binding to its receptor C3aR1, to initiate inflammatory responses. We further discovered that PIPN is attenuated in mice deficient in C3aR1 and that systemic blockage of C3aR1 in wild type rats also reduced PIPN. These results indicated that C3aR1 could be a potentially new therapeutic target for PIPN. In mechanistic studies, we found that paclitaxel treatment upregulated C3aR1 expression on macrophages in sensory ganglion. Macrophages are emerging as a novel therapeutic target for chronic pain. All these data, taken together, lead us to hypothesize that paclitaxel treatment activates C3 to produce C3a to activate sensory ganglion macrophages through C3aR1 signaling, which then sensitize sensory neurons to mediate pain in PIPN. Thus, selectively inhibiting sensory ganglion C3aR1 signaling could prevent or treat PIPN. This project will provide a solid foundation for future development of complement-based therapeutics to prevent or treat PIPN and ultimately to improve survivorship and quality of life from cancer chemotherapy.