Purpose. Microcystic macular edema (MME), originally described in British literature as microcystic macular oedema (MMO), defines microcysts in the inner nuclear layer (INL) of the retina. Microcystic macular edema was described in multiple sclerosis (MS), but can be found in numerous disorders. The presence of MME has important prognostic and therapeutic implications; however, the differential diagnosis is unknown. This study aimed to describe the clinical spectrum of MME. Methods. A single-center, retrospective cohort study. A bootstrap analysis was performed to reduce the 5865 patients (22,376 scans), who had undergone OCT imaging between January 2010 and February 2013, to a representative dataset. The presence of MME was rated by independent observers. Results. The dataset consisted of 1368 patients (mean age 62, range, 4-101 years), 2589 eyes and 6449 scans. Microcystic macular edema was present in 133/1303 (10%) of patients and 0/ 65 (0%) of healthy controls. The interrater agreement for detecting MME was substantial (kappa 0.6) and could be further improved after refining the criteria (kappa 0.8). The clinical spectrum included age-related macular degeneration, epiretinal membranes, postoperative lesions, diabetic retinopathy, vascular occlusion, MS (with/without optic neuritis), optic neuropathy, central serous chorioretinopathy, medication, and miscellaneous causes. The longitudinal pattern of MME was transient (84%) or static. Microcystic macular edema could be associated with an increase or decrease in INL thickness and was predominantly located nasally (48%) and/or temporally (50%). Conclusions. This study substantially widened the clinical spectrum of MME. Diagnostic criteria were refined and validated. The associated phenotype may imply Müller cell dysfunction within the watershed zone. The longitudinal data and evidence from previous studies suggest follow-up of these patients and their visual function. © 2014 The Association for Research in Vision and Ophthalmology, Inc.