The phagocytosis of biodegradable albumin (Alb) microspheres by peripheral blood cells (neutrophils and monocytes) and mouse macrophage cells (peritoneal and lung macrophages) as a carrier matrix in drug targeting applications was investigated. Glutaraldehyde crosslinking was used to produce albumin microspheres with different sizes. Plain (nonmodified) microspheres with diameters of 1, 2, and 4 pm were cultured with cells and their uptake was determined as 8, 5, and 1 particles/cell, respectively. Albumin microspheres (2 pin diameter) were also modified with various opsonization and passivation agents, such as fibronectin (Fn), amicasine, and poly(ethylene glycol) (PEG). Plain, Alb-PEG, Alb-Fn, and Alb-amicasine microspheres were phagocytized by monocytes and neutrophils and the number of particles taken up by each cell significantly increased for Alb-Fn microspheres with respect to the plain microspheres. No significant phagocytosis was observed for Alb-PEG microspheres. The number of particles taken up by each cell was less than the plain and amikacin modified albumin microspheres. Almost zero uptake was obtained for the phagocytosis of Alb-PEG microspheres with lung and peritoneal macrophages. For phagocytosis of plain and other modified particles by the macrophages, although the number of particles taken up by each cell increased with respect to those with neutrophils and monocytes, similar tendencies were also obtained.