The effect of a high, i.v. dose of extruded multilamellar liposomes (1.1 g lipid/kg body wt) upon the subsequent ability of mouse tissues to take-up or bind a second i.v. dose of similar liposomes encapsulating 14C-inulin was studied in vivo. The 1st and 2nd doses were separated by 1.5 or 24 h. All tissue levels were measured 1 h after the 2nd dose. Controls received only the 2nd dose. When the 2 doses were separated by 1 h, 14C-levels in liver were depressed 6-fold and blood levels rose 29-fold relative to controls. Spleen uptake of liposomes increased to 3 times control levels. When the 2 doses were separated by 24 h, the 1st dose had only a minimal effect on the disposition of the 2nd dose. The results are consistent with a reversible blockade of hepatic, but not spleenic uptake and/or binding sites, by the 1st dose and indicate that adjusting a liposome dose (i.e., number of liposomes) or use of a drug-free liposome pre-dose may be a useful technique for reducing hepatic uptake, increasing the circulation life time and/or modifying the tissue disposition properties of therapeutic liposomes without changing liposome composition or size.