In the treatment of peritoneal carcinomatosis, systemic chemotherapy is not quite effective due to the poor penetration of cytotoxic agents into the peritoneal cavity, whereas intraperitoneal administration of chemotherapeutic agents is generally accompanied by quick absorption of the free drug from the peritoneum. Local delivery of drugs with controlled-release delivery systems like liposomes could provide sustained, elevated drug levels and reduce local and systemic toxicity. In order to achieve an ameliorated liposomal formulation that results in higher peritoneal levels of the drug and retention, vesicles composed of different phospholipid compositions (distearoyl DSPC; dipalmitoyl DPPC; or dimiristoylphosphatidylcholine DMPC) and various charges (neutral; negative, containing distearoylphosphatidylglycerol DSPG; or positive, containing dioleyloxy trimethylammonium propane DOTAP) were prepared at two sizes of 100 and 1000 nm. The effect of surface hydrophilicity was also investigated by incorporating PEG into the DSPC-containing neutral and charged liposomes. Liposomes were labeled with 99mTc and injected into mouse peritoneum. Mice were then sacrificed at eight different time points, and the percentage of injected radiolabel in the peritoneal cavity and the tissue distribution in terms of the percent of the injected dose/gram of tissue (%ID/g) were obtained. The ratio of the peritoneal AUC to the free label ranged from a minimum of 4.95 for DMPC/CHOL (cholesterol) 100 nm vesicles to a maximum of 24.99 for DSPC/CHOL/DOTAP 1000 nm (DOTAP 1000) vesicles. These last positively charged vesicles had the greatest peritoneal level; moreover, their level remained constant at approximately 25% of the injected dose from 2 to 48 h. Among the conventional (i.e., without PEG) 100 nm liposomes, the positively charged vesicles again showed the greatest retention. Incorporation of PEG at this size into the lipid structures augmented the peritoneal level, particularly for negatively charged liposomes. The positively charged PEGylated vesicles (DOTAP/PEG 100) had the second-greatest peritoneal level after DOTAP 1000; however, their peritoneal-to-blood AUC ratio was low (3.05). Overall, among the different liposomal formulations, the positively charged conventional liposomes (100 and 1000 nm) provided greater peritoneal levels and retention. DOTAP/PEG100 may also be a more efficient formulation because this formulation can provide a high level of anticancer drug into the peritoneal cavity and also can passively target the primary tumor. Peritoneal level and tissue distribution of classical and PEGylated liposomes with different phospholipid compositions and charges at two sizes (100 nm, A; and 1000 nm, B), were investigated after i.p. injection to mice. Positively charged conventional liposomes provided greater peritoneal levels and retention. Display omitted