To compare four screening strategies for diabetic macular edema (DME).Patients attending diabetic retinopathy screening were recruited and received macular optical coherence tomography (OCT), in addition to visual acuity (VA) and fundus photography (FP) assessments, as part of the standard protocol. Two retina specialists provided the reference grading by independently assessing each subject's screened data for DME. The current standard protocol (strategy A) was compared for sensitivity, specificity, quality-adjusted life-year (QALY) gained, and incremental cost-effectiveness ratio (ICER) with three alternative candidate protocols using a simulation model with the same subjects. In strategy B, macular hemorrhage or microaneurysm on FP were removed as surrogate markers for possible DME. Strategy C used best-corrected instead of habitual/pinhole VA and added central subfield thickness (CST) >290 μm on OCT in suspected cases as a confirmation marker for possible DME. Strategy D used CST >290 μm OCT in all subjects as a surrogate marker for suspected DME.We recruited 2,277 subjects (mean age 62.80 ± 11.75 years, 43.7% male). The sensitivities and specificities were 40.95% and 86.60%, 22.86% and 95.63%, 32.38% and 100%, and 74.47% and 98.34% for strategy A, B, C, and D, respectively. The costs (in U.S. dollars) of each QALY gained for strategy A, B, C, and D were $7,447.50, $8,428.70, $5,992.30, and $4,113.50, respectively.The high false-positive rate of the current protocol generates unnecessary referrals, which are inconvenient for patients and costly for society. Incorporating universal OCT for screening DME can reduce false-positive results by eightfold, while improving sensitivity and long-term cost-effectiveness.