Bone-specific drug delivery is important for the treatment of osteoporosis and osseous metastases. However, there have been limitations in the design of drug carriers having bone affinity. We synthesized amphiphilic polyphosphoester ionomers (CH-PHE) and modified them to 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) vesicles. The ζ-potential of the vesicles was decreased by immobilization of CH-PHE; the amount was influenced by the structure and fraction of CH-PHE. The release rate of 5-carboxyfluorescein from the vesicles could be controlled by changing the fraction of DOPC and CH-PHE. In particular, the release of CF from DOPC vesicles containing 3% CH-PHE was most reduced. In addition, the enzymatic degradation of DOPC was reduced by immobilization with polyphosphoester ionomers; enzyme tolerance was increased with an increase in the molar fraction of polyphosphoester ionomers. Hemolytic activity of the phospholipid vesicles bearing CH-PHE was infrequently observed and was similar to that of the DOPC vesicles. Although a decrease in the viability of mouse osteoblastic cells (MC3T3-E1) in contact with the vesicles bearing CH-PHE was observed when the DOPC concentration of the vesicles bearing 20 mol % CH-PHE with highly ionized units was greater than 200 μM, the cytotoxicity was diminished by sodium salt formation of the CH-PHE. The affinity of the vesicles to calcium deposits generated by MC3T3-E1 cells was significantly improved by the immobilization polyphosphoesters. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.