Silver nanowires (AgNWs) are increasingly being used in the production of optoelectronic devices, with manufacturing processes posing a risk for occupational exposures via inhalation. Although some studies have explored the environmental effects of AgNWs, few data exist on human health effects. Alveolar macrophages are central in the clearance of inhaled fibers from the lungs, with frustrated phagocytosis often stated as a key determinant for the onset of inflammatory reactions. However, the mechanisms through which fully ingested AgNWs interact with, degrade, and transform within primary macrophages over time, and whether the reactivity of the AgNWs arises due to ionic or particulate effects, or both, are poorly understood. Here, a combination of elemental quantification, 3D tomography, analytical transmission electron microscopy (TEM), and confocal microscopy were employed to monitor the uptake, intracellular Ag+ availability, and processing of AgNWs of two different lengths (1 and 10 μm) inside human monocyte-derived macrophages (HMMs). Using AgNO3 and spherical silver nanoparticles (AgNPs) as a comparison, the amount of total bioavailable/intracellular Ag highly correlated to the cytotoxicity of AgNWs. The 10 μm AgNWs were completely internalized in HMMs, with numerous lysosomal vesicles observed in close vicinity to the AgNWs. Following cellular uptake, AgNWs dissolved and transformed intracellularly, with precipitation of AgCl as well as Ag2S. These transformation processes were likely due to AgNW degradation in the acidic environment of lysosomes, leading to the release of Ag+ ions that rapidly react with Cl– and SH– species of the cell microenvironment. Our data suggest that, in HMMs, not only frustrated phagocytosis but also the extent of intracellular uptake and dissolution of AgNWs dictates their cytotoxicity.