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PURPOSE To evaluate whether combining spectral-domain optical coherence tomography (SD-OCT) with monoscopic fundus photography using a non-mydriatic camera (MFP-NMC) improves the accuracy of diabetic macular edema (DME) referrals in a teleophthalmology diabetic retinopathy screening program. METHODS We conducted a cross-sectional study with all diabetic patients aged ≥18 years who attended screening from September 2016 to December 2017. We assessed DME according to the three MFP-NMC and the four SD-OCT criteria. The sensitivity and specificity obtained for each criterion were estimated by comparing them with the ground truth of DME. RESULTS This study included 3918 eyes (1925 patients; median age, 66 years; interquartile range, 58-73; females, 40.7%; once-screened, 68.1%). The prevalence of DME ranged from 1.22% to 1.83% and 1.54% to 8.77% on MFP-NMC and SD-OCT, respectively. Sensitivity barely reached 50% in MFP-NMC and less for the quantitative criteria of SD-OCT. When macular thickening and anatomical signs of DME were considered, sensitivity increased to 88.3%, and the false DMEs and non-gradable images were reduced. CONCLUSIONS Macular thickening and anatomical signs showed the highest suitability for screening, with a sensitivity of 88.3% and a specificity of 99.8%. Notably, MFP-NMC alone missed half of the true DMEs that lacked indirect signs.