A common clinical phenotype of several neurodegenerative and systemic disorders including Alzheimer's disease and atherosclerosis is the abnormal accumulation of extracellular material, which interferes with routine cellular functions. Similarly, patients with age-related macular degeneration (AMD), the leading cause of vision loss among the aged population, present with extracellular lipid- and protein-filled basal deposits in the back of the eye. While the exact mechanism of growth and formation of these deposits is poorly understood, much has been learned from investigating their composition, providing critical insights into AMD pathogenesis, prevention, and therapeutics. We identified human osteopontin (OPN), a phosphoprotein expressed in a variety of tissues in the body, as a newly discovered component of basal deposits in AMD patients, with a distinctive punctate staining pattern. OPN expression within these lesions, which are associated with AMD disease progression, were found to co-localize with abnormal calcium deposition. Additionally, OPN puncta colocalized with an AMD risk-associated complement pathway protein, but not with apolipoprotein E or vitronectin, two other well-established basal deposit components. Mechanistically, we found that retinal pigment epithelial cells, cells vulnerable in AMD, will secrete OPN into the extracellular space, under oxidative stress conditions, supporting OPN biosynthesis locally within the outer retina. Finally, we report that OPN levels in plasma of aged (non-AMD) human donors were significantly higher than levels in young (non-AMD) donors, but were not significantly different from donors with the different clinical subtypes of AMD. Collectively, our study defines the expression pattern of OPN in the posterior pole as a function of disease, and its local expression as a potential histopathologic biomarker of AMD.