Itraconazole (ICZ) is commonly used for the treatment of fungal infections, particularly in immunocompromised patients. In addition, ICZ has been recently found to have antiangiogenic effects and is currently being tested as a new chemotherapeutic agent in several cancer clinical trials. We have previously shown that ICZ impaired complex N-linked glycosylation processing, leading to the accumulation of high-mannose glycoproteins on the surface of macrophages (Møs). This investigation was directed at determining the effects of ICZ on phagocytosis as a major function of Møs. We found a significant decrease in the phagocytosis of opsonized bacterial particles in ICZ-treated murine Møs in comparison with nontreated Møs. Furthermore, the impairment of phagocytosis was associated with a decrease in cell surface expression of Fcγ receptors (FcγRs) as well as alteration of their glycosylation pattern. Concomitantly, a reduction in all three isoforms of the FcγR family (i.e., Fcgr1, Fcgr2, and Fcgr3) mRNA levels was observed after incubation with ICZ. The effect of ICZ on phagocytosis and FcγR expression was reversed by addition of low-density lipoprotein. These studies indicate that ICZ treatment certainly has a dramatic effect on macrophage function, which could result in a potential impairment of the immune system’;s ability to respond to pathogens and may lead to an elevated incidence of infections.