Particulate drug carriers have a pronounced tendency to localize in the mononuclear phagocyte system and chronic administration of such carriers can result in reticuloendothelial (RE) blockade. In a previous study (Allen et al., J. Pharmacol. Exp. Therap., 229, 267, 1984) we have examined the ability of chronic i.v. administration of liposomes of a variety of compositions to cause RE blockade in mice. In this communication we report on the time course of histological changes in liver accompanying chronic liposome administration in samples collected at the time of our previous studies. The predominant histological feature was the appearance of a granulomatous reaction in liver. Granulomas were frequent in liver tissue of mice receiving 2 or more injections of sphingomyelin:phosphatidylcholine, 4:1 or distearoylphosphatidylcholine:cholesterol, 1:1 liposomes, but disappeared shortly after termination of liposome injections. In mice receiving phosphatidylcholine:cholesterol, 2:1 liposomes no granulomas in liver were apparent during the injection course (10 injections of 2 mg phospholipid each over 25 days) but granulomatous inflammation of the liver became apparent 2 weeks after the last injection and had not resolved by 9 weeks post-injection. The appearance of granulomas was correlated with depression of phagocytic index and their disappearance was correlated with normalization or stimulation of reticuloendothelial function. These observations may be related to the rate of phospholipid metabolism for the various phospholipid types or to the nature of phospholipid metabolites.