The cyclic hexapeptides PMX53 and PMX205 are potent noncompetitive inhibitors of complement C5a receptor 1 (C5aR1). They are widely utilized to study the role of C5aR1 in mouse models, including central nervous system (CNS) disease, and are dosed through a variety of routes of administration. However, a comprehensive pharmacokinetics analysis of these drugs has not been reported. In this study, the blood and CNS pharmacokinetics of PMX53 and PMX205 were performed in mice following intravenous, intraperitoneal, subcutaneous, and oral administration at identical doses. The absorption and distribution of both drugs were rapid and followed a two-compartment model with elimination half-lives of ∼20 min for both compounds. Urinary excretion was the major route of elimination following intravenous dosing with ∼50% of the drug excreted unchanged within the first 12 h. Oral bioavailability of PMX205 was higher than that of PMX53 (23% versus 9%), and PMX205 was also more efficient than PMX53 at entering the intact CNS. In comparison to other routes, subcutaneous administration of PMX205 resulted in high bioavailability (above 90%), as well as prolonged plasma and CNS exposure. Finally, repeated daily oral or subcutaneous administration of PMX205 demonstrated no accumulation of drug in blood, the brain, or the spinal cord, promoting its safety for chronic dosing. These results will be helpful in correlating the desired therapeutic effects of these C5aR1 antagonists with their pharmacokinetic profile. It also suggests that subcutaneous dosing of PMX205 may be an appropriate route of administration for future clinical testing in neurological disease.