Hyperreflective foci (HRF) features in macular edema associated with different etiologies may indicate the disease pathogenesis and help to choose proper treatment. The goal of this study is to investigate the retinal microstructural features of macular edema (ME) secondary to multiple etiologies with spectral-domain optical coherence tomography (SD-OCT) and analyze the origin of HRF in ME.This was a retrospective study. SD-OCT images were reviewed to investigate macular microstructural features such as the number and distribution of HRF and hard exudates and the internal reflectivity of the cysts. The differences in microstructural features between groups and the correlations between the number of HRF and other parameters were analyzed.A total of 101 eyes with ME from 86 diabetic (diabetic macular edema, DME) patients, 51 eyes from 51 patients with ME secondary to branch retinal vein occlusion (branch retinal vein occlusion-macular edema, BRVO-ME), 59 eyes from 58 central retinal vein occlusion (central retinal vein occlusion-macular edema, CRVO-ME) patients, and 26 eyes from 22 uveitis (uveitic macular edema, UME) patients were included in this study. The number of HRF, the frequency of hard exudates and the enhanced internal reflectivity of the cysts were significantly different among the groups. The number of HRF in the DME group was significantly higher than that in the other groups (all P < 0.05). The frequency of hard exudates and enhanced internal reflectivity of the cysts in the DME group were significantly higher than ME secondary to other etiologies (all P < 0.001). Within the DME group, the number of HRF in the patients with hard exudates was significantly higher than that in the patients without hard exudates (P < 0.001).HRF detected with SD-OCT were more frequent in DME patients than in BRVO-ME, CRVO-ME, or UME patients. The occurrence of HRF was correlated with the frequency of hard exudates. HRF may result from the deposition of macromolecular exudates in the retina, which is speculated to be a precursor of hard exudates.© 2022. The Author(s).