Liposomes are artificially generated vesicles entrapping aqueous solutions within lipid bilayer membranes. A major potential use of liposomes is for the delivery of antineoplastic agents to malignant tissue. However, liposome-cell interactions with both normal and neoplastic cells must be characterized in vitro to identify neoplastic tissues for which this approach may be most applicable in vivo. In this study, mouse melanoma-liposome interactions were examined in vitro. Small, unilamellar vesicle liposomes of three different phospholipid-cholesterol compositions were synthesized incorporating an aqueous phase fluorescent marker. Mouse melanoma had a significantly greater affinity for phosphotidylcholine-cholesterol liposomes than did mouse hepatocytes, as determined by comparing quantities of free intracellular 6-carboxyfluorescein in cells after a 15-min incubation with each of the three different liposome preparations (P less than 0.001). In addition, the efficiency of liposome internalization, calculated as the percentage of total cell-associated 6-carboxyfluorescein present as free, intracellular 6-carboxyfluorescein, was significantly greater for melanoma than for hepatocytes with all three liposome preparations (P less than 0.05). Therefore, in vitro liposome uptake by melanoma depends on lipid characteristics of the liposome preparation. Because melanoma uptake of liposomes appears to be a very efficient process in vitro, liposomes may be a useful vesicle for delivery of antineoplastic agents to melanoma in vivo.