Purpose To determine if treatment with a photobiomodulation (PBM) device results in greater improvement in central subfield thickness as compared with placebo in eyes with center-involved diabetic macular edema (CI-DME) and good vision Design Phase 2 randomized clinical trial Participants Participants had CI-DME and visual acuity (VA) 20/25 or better in the study eye and were recruited from 23 clinical sites in the US. Methods One eye of each participant was randomly assigned 1:1 to a 670-nm light-emitting PBM eye patch or an identical device emitting broad-spectrum white light at low power. Treatment was applied for 90 seconds twice daily for 4 months. Main Outcome Measure Change in central subfield thickness (CST) on spectral-domain optical coherence tomography (OCT) at 4 months. Results From April 2019 to February 2020, 135 adults were randomly assigned to either PBM (N = 69) or placebo (N = 66); median age was 62, 37% were female and 82% were white. Median device compliance was 92% with PBM and 95% with placebo. OCT CST increased from baseline to 4 months by a mean (SD) of 13 (53) μm in PBM eyes and 15 (57) μm in placebo eyes (mean difference (95% CI) = -2 (-20 to 16) μm; p = .84). CI-DME, based on DRCR Retina Network sex and machine-based thresholds, was present in 61 (90%) of PBM eyes and 57 (86%) of placebo eyes at 4 months (adjusted odds ratio (95% CI) = 1.30 (0.44 to 3.83); p = .63). Visual acuity decreased by a mean (SD) of -0.2 (5.5) letters and -0.6 (4.6) letters in the PBM and placebo groups, respectively (difference (95% CI) = 0.4 (-1.3 to 2.0) letters; p = .64). There were eight adverse events possibly related to the PBM device, and two adverse events possibly related to the placebo device. None were serious. Conclusions PBM as given in this study, while safe and well tolerated, was not found to be effective for the treatment of CI-DME in eyes with good vision.