(1) Purpose: To determine the “retinal thickness deviation” (RTD) in diabetic macular edema (DME) eyes treated with intravitreal therapy and to establish associations between RTD and best-corrected visual acuity (BCVA). (2) Methods: We conducted a retrospective study, including consecutive patients with DME eyes undergoing intravitreal therapy with two years of follow-up. BCVA and central subfield thickness (CST) were collected at baseline and at 12 months and 24 months of follow-up. RTD was calculated as the absolute difference between measured and normative CST values at each time point. Linear regression analyses were performed between RTD and BCVA and between CST and BCVA. (3) Results: One hundred and four eyes were included in the analysis. The RTD was 177.0 (117.2) μm at baseline, 97.0 (99.7) μm at 12 months and 89.9 (75.3) μm at 24 months of follow-up (p< 0.001). RTD showed a moderate association with BCVA at baseline (R2= 0.134,p< 0.001) and 12 months (R2= 0.197,p< 0.001) and a substantial association at 24 months (R2= 0.272,p< 0.001). The CST showed a moderate association with BCVA at baseline (R2= 0.132,p< 0.001) and 12 months (R2= 0.136,p< 0.001), while the association was weak at 24 months (R2= 0.065,p= 0.009). (4) Conclusions: RTD showed a good association with visual outcome in patients with DME eyes undergoing intravitreal treatment.