PURPOSE: To estimate the short-term variability of macular thickness in eyes with refractory and regressed diabetic macular edema (DME). METHODS: In this retrospective review of consecutive cases from a retina practice, optical coherence tomography (OCT) measurements of macular thickness were extracted from the clinical charts of patients with refractory DME and regressed DME. Variation in macular thickness was defined as maximal central subfield mean thickness (CSMT) minus minimal CSMT during a period of observation in which clinical macular status did not change. RESULTS: There were 36 eyes of 29 patients in the refractory DME group and 93 eyes of 93 patients in the regressed DME group. Median intervals during which macular status was unchanged and OCTs were collected were 7 months for the refractory DME group and 22 months for the regressed DME group. Baseline CSMTs were 321 μm for the refractory DME group and 217 μm for the regressed DME group. The median variation in CSMT was 89 μm for the refractory DME group and 19 μm for the regressed DME group. Results for total macular volume paralleled those for CSMT. CONCLUSIONS: In consonance with eyes having treatment-naïve DME, eyes with refractory DME have short-term fluctuation in macular thickness larger than OCT measurement variability. In eyes with regressed DME, short-term fluctuation is less than in eyes with refractory DME, yet can also exceed measurement variability. This information is clinically important in deciding whether subsequent treatment is indicated.