Purpose: To characterize factors that may be associated with optimal or suboptimal response to ranibizumab intravitreal injections in diabetic macular edema (DME). Methods: Fifty-nine eyes with DME treated with ranibizumab were included. All underwent best-corrected visual acuity (BCVA) assessment and optical coherence tomography (OCT) at baseline, 3 and 6 months. Central retinal thickness (CRT) was assessed at each visit, and OCT images were classified according to their morphological patterns. Results: A mean BCVA increase of 4.78 and 5.52 letters, and a CRT decrease of 80.25 and 106.12 µm were found after 3 and 6 months of treatment (p < 0.001). BCVA improvement was found to be dependent on baseline BCVA and the degree of CRT decrease. Twenty-six eyes (44%) showing a CRT decrease ≥20% improved BCVA by 10.3 ± 13.0 letters, whereas 33 eyes (56%) with a CRT decrease <20% had BCVA improvement of 1.8 ± 7.2 letters (odds ratio = 3.31). Conclusions: The degree of CRT decrease obtained by spectral-domain OCT identifies well the optimal responders to intravitreal ranibizumab and predicts BCVA improvement after treatment.