Background: To evaluate the prognostic factors for the best-corrected visual acuity (BCVA) and foveal average retinal thickness after vitrectomy with internal limiting membrane (ILM) peeling for diabetic macular edema. Design: Retrospective, single-center study. Participants: This study involved 31 eyes of 27 patients who had undergone vitrectomy with ILM peeling between January 2005 and March 2008. Methods: Relationships between preoperative systemic or ocular factors and BCVA or foveal average retinal thickness before and 6 months after the operation were evaluated. Main Outcome Measures: BCVA and foveal average retinal thickness before and 6 months after the operation. Results: The mean logarithm of the minimum angle of resolution improved from 0.84 ± 0.64 (mean ± standard deviation) preoperatively to 0.64 ± 0.38 six months postoperatively (p = 0.393). Foveal average retinal thickness significantly improved from 473 ± 146 μm preoperatively to 318 ± 108 μm 6 months after the operation (p < 0.0001). Preoperative foveal average retinal thickness was significantly thicker with cardiovascular disease or cerebral infarction (p = 0.0019) or cystoid macular edema (p = 0.0028), while preoperative BCVA was significantly lower when an epiretinal membrane (p = 0.042) was present. Foveal average retinal thickness at the 6-month follow-up was significantly thicker when patients had a higher body mass index (p = 0.0088), were not on dialysis (p = 0.012), or did not have proliferative diabetic retinopathy (p = 0.013). BCVA at the 6-month follow-up was significantly lower in the group with no history of diabetes treatment until diabetic retinopathy was found (p = 0.023) and in patients with a higher preoperative glycosylated hemoglobin (p = 0.033). Conclusions: Preoperatively, BCVA and foveal average retinal thickness were primarily associated with ocular factors, while they were strongly associated with systemic factors, postoperatively. Ocular factor improvements may be related to the surgical procedure.