© 2016 Elsevier Inc. All rights reserved. Purpose To describe the natural course, visual outcomes, and anatomic changes and provide histologic correlates in eyes with intraretinal hyperreflective foci associated with acquired vitelliform lesions. Design Retrospective cohort study and imaging-histology correlation in a single donor eye. Methods participants: Patients with intraretinal hyperreflective foci and acquired vitelliform lesions from 2 tertiary referral centers were evaluated from January 2002 to January 2014. main outcome measures: The chronology of clinical and imaging features of retinal anatomic changes and the pattern of intraretinal hyperreflective foci migration were documented using spectral-domain optical coherence tomography (OCT). One donor eye with intraretinal hyperreflective foci was identified in a pathology archive by ex vivo OCT and was studied with high-resolution light and electron microscopic examination. Results Intraretinal hyperreflective foci were associated with acquired vitelliform lesions in 25 of 254 eyes (9.8%) with a strong female preponderance (86% of patients). Focal disruptions to the ellipsoid zone and external limiting membrane overlying the acquired vitelliform lesions were observed prior to the occurrence of intraretinal hyperreflective foci in 75% of cases. Histologic evaluation showed that intraretinal hyperreflective foci represent cells of retinal pigment epithelium origin that are similar to those found in the vitelliform lesions themselves and contain lipofuscin granules, melanolipofuscin granules, and melanosomes. The occurrence of intraretinal hyperreflective foci was not a significant determinant of final visual acuity (P =.34), but development of outer retinal atrophy was (P =.003). Conclusions Intraretinal hyperreflective foci associated with acquired vitelliform lesions are of retinal pigment epithelium origin, and the natural course and functional changes are described.