Purpose: To investigate longer-term functional and morphological outcomes and their predictors in diabetic macular edema (DME) following a treat and extend regimen (TER) without loading dose under ranibizumab. Methods: Patient data were reviewed and analyzed retrospectively over a period of 24 months after initiation of TER. Best-corrected visual acuity (BCVA), treatment frequency as well as quantitative and qualitative Spectral-domain Optical Coherence Tomography parameters were assessed. Results: 118 eyes of 87 patients were included. A mean of 9.742.13 injections in the first and 7.632.29 in the second year were applied. There were significant gains of BCVA and reductions in central retinal thickness from baseline to month 12 and 24 (all p<0.001). Percentage of eyes with an intact inner-/outer segment (IS/OS) junction increased from 15.3% at baseline to 42.1% at month 24 (p<0.001). An intact IS/OS junction at baseline increased the probability of having a dry retina after 12 months by 79.3% (p=0.017) and after 24 months by 88.1% (p=0.040). Less IS/OS disruption at baseline predicted longer maximum recurrence-free treatment intervals at 2 years (r=-0.345, p<0.001) and better BCVA at one year (r=-0.347, p<0.001). Baseline bigger intraretinal cysts were associated with more IS/OS disruption at 24 months (r=0.305, p=0.007). Younger age and lower BCVA at baseline were predictive for a higher BCVA gain at 24 months (p=0.046, p<0.001). Conclusion: Ranibizumab applied in a TER without loading dose in DME significantly improves visual acuity and retinal anatomical structure throughout two years. The evaluated predictors might help to guide routine clinical treatment in DME.