Purpose: To evaluate the impact of anti–vascular endothelial growth factor therapy on the refractive error in eyes with diabetic macular edema. Methods: Post hoc analysis of Diabetic Retinopathy Clinical Research protocol T. Spherical equivalent (SE) was calculated for study and fellow eyes at baseline, 1-year, and 2-year visits. The SE change of the eyes with edema was compared with those with resolved edema. The correlation between refractive error changes and central subfield thickness was evaluated. Results: Among 543 study eyes, SE changed from −0.17 (2.04) D at baseline visit to −0.16 (2.14) D at 2 years giving a hyperopic shift of 0.04 (0.82) D (P = 0.022). Among fellow eyes, mean (SD) SE changed from −0.19 (2.1) D at baseline to −0.11 (2.1) D at 2 years, giving a hyperopic shift of 0.12 (0.84) D (P = 0.001). No significant difference in SE shift was found between eyes with and without edema at 2 years in phakic (0.12D and 0.08 D, P = 0.87) and pseudophakic eyes (−0.24D and −0.08D, P = 0.30). The SE shift was not correlated with central subfield thickness change at the end of the second year (r = 0.02, P = 0.62). Conclusion: Diabetic macular edema patients have minimal changes in refractive error. The correction of refractive error may be considered during treatment, regardless of the presence of edema.