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Objective. To investigate the systemic and ocular factors that affect the response to intensive aflibercept treatment in diabetic macular edema (DME) in a real-world setting. Methods. This retrospective cohort study evaluated 30 eyes of 23 patients with DME who underwent intensive intravitreal aflibercept injections (five monthly loading doses). Treatment response was assessed by central retinal thickness (CRT) and best-corrected visual acuity (BCVA) at each monthly visit. The patients were categorized as good (<300 μm) and suboptimal (≥300 μm) responders based on CRT after the loading phase. Baseline systemic and ocular factors associated with treatment response were investigated. Results. The mean CRT and BCVA significantly improved after five loading injections ( 486.87 ± 95.46 to 334.90 ± 69.47  μm and 0.51 ± 0.30 to 0.35 ± 0.25 LogMAR, respectively, all p < 0.05 ). During 12 months of follow-up, 16 eyes (53.33%) maintained CRT without additional treatment. Eyes with diabetes mellitus (DM) for ≥15 years, estimated glomerular filtration rate eGFR < 80  mL/min/1.73 m2, serum creatinine ≥ 0.95  mg/dL and potassium ≥ 4.7  mmol/L, and presence of epiretinal membrane (ERM) were more likely to have a suboptimal response to the treatment. Conclusions. Five monthly loading doses of intravitreal aflibercept injection provided significant anatomical and visual improvements in patients with DME. Patients with longer DM duration, lower eGFR, higher serum creatinine or potassium levels, or ERM were predisposed to a suboptimal treatment response. Individual response to intensive aflibercept treatment for DME can be predicted by these systemic and ocular risk factors.