AIM: To explore the efficacy of minimally invasive vitrectomy (MIV) with or without internal limiting membrane (ILM) peeling on the treatment of diabetic macular edema (DME) in proliferative diabetic retinopathy (PDR) combining with preoperative anti-vascular endothelial growth factor (anti-VEGF) injection. METHODS: Totally 132 eyes (132 patients) diagnosed PDR with DME were included between June 2015 and June 2018 in Tianjin Eye Hospital. The single MIV treatment group included 68 eyes and the MIV combined with ILM peeling group included 64 eyes. Anti-VEGF drugs were injected intravitreally 1wk before the operation and the period of follow-up was 1 to 3y. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), total macular volume (TMV), macular edema (ME) severity, intraocular pressure (IOP), and complications were recorded. Prognostic factors of visual acuity following ILM peeling were analyzed. RESULTS: The BCVA was higher than preoperative values at 1, 3, 6, and 12mo after surgery in both groups (all P<0.05). At 6 and 12mo, the BCVA of the combined group was significantly higher than that of the MIV only group (0.52±0.23 vs 0.64±0.29 logMAR, P=0.011 in 6mo; 0.41±0.25 vs 0.52±0.25 logMAR, P=0.008 in 12mo). Mean CRT values postoperative were significantly lower than preoperative values in both groups from the 1st month (1mo 397.65±106.18 vs 451.94±118.88 μm in MIV only group; 388.88±108.68 vs 464.36±111.53 μm in combined group; both P<0.05) and decreased gradually. The differences between the two groups were statistically significant at 3, 6, and 12mo (P=0.004, 0.003, 0.00 respectively). The TMV was decreased from the 3rd month in the single treatment group (3mo 11.14±1.66 vs 12.20±2.09 mm3, P<0.05). At 12mo, the proportion of eyes with edema that had CRT more than 350 μm was significantly lower than before surgery (13.24% vs 77.94% in MIV only group; 1.56% vs 81.25% in combined group; both P<0.05). There was no significant difference in the recurrence incidence of macular epiretinal membrane, ME, transient IOP increase, vitreous rebleeding, or traction retinal detachment between the two groups. BCVA after ILM excision was positively correlated with the CRT and ME degree before and after surgery (r=0.430, 0.485, respectively; P<0.05). CONCLUSION: MIV combined with ILM peeling accelerates the absorption of ME, improves vision, reduces the postoperative CRT and TMV, and reduces the recurrence rate of postoperative ME.