Purpose: Age-related macular degeneration (AMD) is one of the leading causes of blindness in the elderly population aged ≥60 years. Previous studies have shown that retinal pigment epithelial cell (RPE) degeneration is one of the early and crucial stages in AMD. It has been suggested that microglia and macrophages may be involved in the impairment of RPE, but how they and RPE are influenced by other factors present as AMD develops is unclear. Therefore the purpose of this study was to determine the role of macrophages in RPE degeneration in the presence of cytokines and oxidative stress likely to be present as AMD develops. Methods: A co-culture model system was set up using bone marrow-derived macrophages and brain or retinal microglia cultured with RPE. Cytokines (IL-1β, TNF-α, IFN-γ, and IL-6) and oxidized low-density lipoprotein were included in the culture at concentrations estimated to be likely during AMD, and apoptosis of RPE cells determined using flow cytometry to detect annexin V. Results: Macrophages were shown capable of enhancing the apoptosis of RPE cells in a contact-dependent manner. IL-1β, IFN-γ, IL-6, TNF-α, and oxLDL increased apoptosis; they increased RPE cell apoptosis directly, increased the susceptibility of RPE to subsequent apoptosis in the presence of microglia/macrophages, and increased the ability of microglia/macrophages to cause apoptosis. Conclusions: These findings indicate that microglia and macrophages are capable of enhancing the degeneration of RPE, which are crucial in AMD development. However this is dependent on the microenvironment present as AMD develops. © 2016 Taylor & Francis.