The effect of liposome composition on drug delivery to tumors and therapeutic efficacy of liposome-encapsulated anthracyclines was investigated in two murine tumor models: an ascitic tumor (J6456 lymphoma) and a solid carcinoma (M-109). Longevity in circulation correlated positively with high drug levels in the extracellular (ascitic) tumor fluid and with delayed peak tumor levels. Using polyethylene-glycol(PEG)-coated liposomes, liposome stability (drug retention) was found to be an important determinant of therapeutic efficacy, as indicated by the superior survival conferred by high Tm phosphatidylcholines (hydrogenated, dipalmitoyl) over low Tm (egg phosphatidyl-choline). Replacing PEG with another negatively-charged surface headgroup (phosphatidyl-glycerol, phosphatidyl-inositol) resulted in relatively shorter longevity in circulation of the liposome-associated drug, but no detectable differences in anti-tumor efficacy. When neither the surface charged headgroup nor the PEG coating are present, the resulting drug formulation was significantly less effective than PEG and phosphatidylinositol-based formulations in both tumor models. In conclusion, longevity in circulation, as obtained with PEG coating, tends to improve the therapeutic efficacy of liposome-encapsulated anthracyclines. The current therapeutic models were however unable to detect differences between the therapeutic activity of PEG and other liposome formulations with relatively small differences in circulation longevity.