Liposomes are one of the most widely studied drug carriers due to their relative biocompatibility, lack of immune system stimulation, ability to be cell specific, and serve as a protective drug carrier. Due to several physicochemical properties such as size and charge, liposomes naturally target the phagocytic capabilities of macrophages. In the tumor microenvironment, macrophages strongly influence growth and progression, making them an appealing target for drug delivery. Using the natural capability of liposomes to target macrophages, and the knowledge that material properties can alter cellular responses, this work aims to influence macrophage phenotype with arginine-like surface modified DOPE:DOPC liposomes. These liposomes were incubated with interleukin-4 (IL-4) or lipopolysaccharide (LPS) stimulated macrophages and naïve RAW 264.7 macrophages. Macrophage phenotype was determined through arginase activity, tumor necrosis factor (TNF)-α secretion, and nitrite production. With significant variations in the molecular profiles of each activated cell type, these findings suggest that macrophage responses could be altered with small variations in surface functionality of liposomes.