The feasibility of targeting liposomes reconstituted with P0 protein (P0-liposomes) to melanoma cells with high level of intercellular adhesion molecule-1 (ICAM-1) expression was investigated. P0 protein, an immunoglobulin superfamily (IgSF) cell adhesion molecule from peripheral nerve myelin, was used as a model targeting ligand. Liposome uptake by the cells was quantitated using radioactive lipids. The presence of intact P0 protein in the liposome bilayer increased the extent of interaction of liposomes with human M21 (7.80 fold) and A-375 (4.62 fold) melanoma cells compared to control liposomes of same lipid composition but no P0 protein, whereas with MeM 50-10 melanoma cells no significant increase was found (1.70 fold). The extent of binding of P0-liposomes to the melanoma cells correlated with the level of ICAM-1 expression on cells (r2 = 0.9996). M21 and A-375 cells express ICAM-1 (the percentage of stained cells, PSC, was 95% and 85%, respectively), whereas, MeM 50-10 cells do not. P0 protein also increased the interaction of liposomes with P0 protein expressing CHO-X2 cells (4.36 fold, as a positive control) compared to control liposomes. The indirect flow cytometry experiments using biotinylated P0 protein showed that P0 protein itself in solution also binds to M21 cells but does not bind to MeM 50-10 cells. Preincubation of M21 cells with anti-ICAM-1 monoclonal antibody decreased the binding of biotinylated P0 protein to the M21 cells by 35%. P0 protein or its binding domain(s) that mediate the targeting of liposomes through adhesive interactions may be useful for the development of novel types of drug delivery systems. This approach may have relevance in the treatment of metastatic cancers, inflammation and viral diseases, where cell adhesion proteins are over expressed.