The aim of this study was to analyze the outcomes of eyes with visually significant cystoid macular œdema (vs-CMO) after Descemet membrane endothelial keratoplasty (DMEK) in a referral center for keratoplasty in Spain. We conducted a retrospective, single-surgeon case series of eyes that developed post-DMEK vs-CMO performed between January 2011 and December 2020. Data collected included: indication for DMEK; biometric data; ocular comorbidities; past medical history; time to detection of vs-CMO after DMEK (T, weeks); best-corrected visual acuity (BCVA, logMAR) and central retinal thickness (CRT, µm) at diagnosis of vs-CMO, after resolution of CMO, and at last follow-up; and management strategy. Main outcomes analyzed were incidence of vs-CMO, improvement in BCVA and CRT after treatment of vs-CMO. Of 291 consecutive DMEK surgeries, 14 eyes of 13 patients (4.8%) developed vs-CMO. Five patients (38.5%) had history of CMO, and 28.6% of eyes had ophthalmic comorbidities. Median (P25-P75) T was 4 (3–10) weeks. Treatment success was observed in 12/13 eyes (92.3%), two of which required second-line treatment. In successful cases (median time-to-resolution 3.0 (2.0–3.5) months), median BCVA improved from 0.60 (0.40–0.80) logMAR to 0.30 (0.15–0.40) logMAR (p = 0.002) after treatment, and median CRT improved from 582.5 (400.0–655.0) µm to 278.0 (258.0–294.0) µm (p = 0.005). In our study, we found a 4.8% rate of post-DMEK vs-CMO, with most cases occurring in the first 3 months after surgery. Good functional and anatomical outcomes are expected in most eyes, without treatment-related complications or implications in graft outcomes. Additional studies are encouraged to determine a standardized protocol for post-DMEK vs-CMO.