To analyse clinical and tomographic features of diabetic macular edemas (DME) unresponsive to laser photocoagulation. Retrospective study of 43 consecutive eyes presenting with severe DME defined by a macular thickening 450 microm or more, involving the fovea, and associated with either cystoid spaces and/or hard exudates threatening the center of the macula. All 43 eyes underwent subthreshold grid laser therapy (a mean of 2.3 sessions). Mean follow-up was 21 months. Photocoagulation was beneficial in 39% of the eyes (n=17) and failed in 60% (n=26). Comparing these two groups, we found that some tomographic and clinical signs were strikingly more frequent in the unresponsive eyes than in the responsive ones. OCT findings reported foveal thickening greater than 700 microm (38%), subclinical serous foveal detachment (65%), subclinical vitreomacular interface abnormalities (19%) and as clinical signs, 44% of the unresponsive eyes exhibited rapid progression of retinal ischemia preceding ME constitution. Long-standing diffuse DME carries an unfavorable prognosis. In cases of unresponsive DME exhibiting these tomographic and clinical signs, alternative therapies such as intravitreal injections of steroids and/or vitrectomy with posterior hyaloid removal should be considered, instead of iatrogenic and useless iterative grid laser treatments.