Our aim was to develop a novel liposomal drug delivery system containing dextrans to reduce undesirable retention of antineoplastic agents and thus alleviate local tissue damage. At the cell level, diethylaminoethyl-dextran (DEAE-Dx) showed the strongest inhibiting effect on liposome uptake by macrophages among tested dextrans. The distribution of radiolabeled liposomes mixed with dextrans in injection site and draining lymph node was investigated in rats after subcutaneous injection. DEAE-Dx substantially reduced the undesired local retention and promoted the draining of liposome into lymphatics, which was further confirmed by confocal microscopy images revealing the substantial prevention of rhodamine B-labelled liposome sequestration by macrophages in normal lymph node in rats. Pharmacokinetic data indicated the accelerated drainage of liposome through lymphatics back to systemic circulation by mixing with DEAE-Dx. In the toxicological study in rabbits, DEAE-Dx alleviated the local tissue damage caused by liposomal doxorubicin. In conclusion, dextrans, particularly DEAE-Dx, could efficiently enhanced liposomes drainage into lymphatics, which proves themselves as promising adjuvants for lymphatic-targeted liposomal drug delivery system.