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To evaluate the responsiveness of the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) in patients with diabetic macular edema using data from the RIDE and RISE trials.Patients were randomized to monthly intravitreal ranibizumab 0.3 mg, 0.5 mg, or sham injections for 2 years. The NEI VFQ-25 was administered at baseline and at Months 6, 12, 18, and 24. The least-squares mean change in NEI VFQ-25 for ≥15 letters gained or lost was derived from analysis of covariance models.The mean improvement in NEI VFQ-25 composite score associated with a ≥15-letter gain in best-corrected visual acuity over 24 months was 9.0 (95% confidence interval, 6.3–11.7) points in RIDE and 7.1 (95% confidence interval, 4.7–9.6) points in RISE. In patients who lost ≥15 letters, the mean worsening in overall NEI VFQ-25 composite score was −6.6 (95% confidence interval, −13.6 to 0.5) in RIDE and −2.7 (95% confidence interval, −8.9 to 3.5) in RISE.This exploratory analysis of data from the RIDE and RISE studies supports the responsiveness of the NEI VFQ-25 to changes in best-corrected visual acuity over time in patients with diabetic macular edema.