Improper regulation of complement is associated with various pathologies, and the clinical demand for compounds that can regulate complement activation is therefore imperative. Cp40, an analog of the peptide compstatin, inhibits all complement pathways at the level of the central component C3. We have further developed Cp40, using either PEGylation at the N-terminus or insertion of charged amino acids at the C-terminus. The PEGylated analogs are highly soluble and retained their inhibitory activity, with C3b binding affinity dependent on the length of the PEG chain. The addition of two or three residues of lysine, in turn, not only improved the peptide's solubility but also increased the binding affinity for C3b while retaining its inhibitory potency. Three of the new derivatives showed improved pharmacokinetic profiles in vivo in non-human primates. Given their compelling solubility and pharmacokinetic profiles, these new Cp40 analogs should broaden the spectrum of administration routes, likely reducing dosing frequency during chronic treatment and potentially expanding their range of clinical application.