AIM: To compare the effects of yellow (577 nm) subthreshold micropulse laser (SML) and intravitreal (IV) anti-vascular endothelial growth factor (VEGF) treatment in patients with diabetic macular edema (DME) with relatively better visual acuity [best corrected visual acuity (BCVA) ≤0.15 logMAR]. METHODS: The medical records of 76 eyes of 47 patients underwent IV (0.5 mg) anti-VEGF injection or SML for the DME with relatively better BCVA were reviewed. The IV group received three consecutive monthly IV anti-VEGF injections, then were retreated as needed. The laser treatment group was treated at baseline and 3mo, and then retreated at 6 and 9mo if needed. All participants were followed up for one year. The mean BCVA and mean central macular thickness (CMT) values changes over the follow-up were evaluated. RESULTS: Twenty-four and 23 patients were assigned to the SML and IV subgroups, respectively. The mean number of treatments was 3.64±0.76 in SML group and 5.85±1.38 in IV group (P<0.05). The subgroups were similar with regard to the mean BCVA score at baseline and at the 1st and 3rd months, but the score of SML group was better than that of IV group at the 6th, 9th, and 12th months (P<0.05). The decrease in the mean CMT values from baseline values was higher in SML group at the 6th, 9th, and 12th months (P<0.05). CONCLUSION: Yellow SML treatment is superior to IV anti-VEGF injection in DME patients with relatively better BCVA for increasing visual acuity and decreasing CMT at 6, 9, and 12mo. SML can be a good alternative first-line therapy for DME with BCVA ≤0.15 logMAR.