PURPOSE: Tamoxifen-induced retinopathy (TR) and macular telangiectasia type 2 (MacTel) share a highly similar retinal phenotype. In this study, we aimed to evaluate differences and similarities that may point toward underlying mechanisms linking both disease entities. DESIGN: Retrospective, cross sectional study. SUBJECTS: Patients diagnosed with MacTel or TR. METHODS: Patients underwent multimodal retinal imaging, including color fundus photography, spectral-domain OCT, fundus autofluorescence, fluorescein angiography, and OCT angiography (if available). Age, age of onset, best-corrected visual acuity, and bilaterality of changes were evaluated. Patients' eyes were graded for different morphologic characteristics by 4 experienced graders. MAIN OUTCOME MEASURES: Phenotypical characterization and comparison of frequencies of retinal characteristics of TR and MacTel on multimodal imaging. RESULTS: Twenty-eight eyes of 14 patients with TR and 118 eyes of 59 patients with MacTel were included. Age, age of onset, and best-corrected visual acuity were similar in both cohorts. All but 1 patient showed bilateral changes. In patients with MacTel, neurodegenerative changes and vascular alterations were equally present, whereas in patients with TR, neurodegenerative changes usually prevailed. Predilection sites within the central retina differed between the 2 diseases: most findings in patients with TR were limited to the foveal center, whereas changes in patients with MacTel were present throughout a slightly larger region (``MacTel area''), with an epicenter temporal to the foveal center. Distinct morphologic features included the distribution of retinal crystals, the size and position of ellipsoid zone breaks, and the presence of hyperreflective changes on OCT images. Focal hyperpigmentation and neovascular membranes were only present in eyes with MacTel. CONCLUSIONS: Macular telangiectasia and TR share a highly similar retinal phenotype, especially in early disease stages. Subtle differences on multimodal retinal images may help distinguish between these 2 disease entities. Our findings indicate the involvement of Müller cells in both diseases, which may explain the observed phenotypic characteristics and similarities.