PURPOSE: To compare visual acuity (VA) change at 24 months in eyes with clinically significant DME (CSDME) and good VA initially treated versus initially observed in routine clinical practice. METHODS: Retrospective analysis of treatment-naïve eyes with CSDME and good VA (baseline VA ≥ 79 letters), with at least 24 months of follow-up and initially managed with treatment (intravitreal treatment and/or macular laser) or observation with possible treatment after 4 months that were tracked in a prospectively designed observational registry. RESULTS: We identified 150 eligible eyes (98 initially observed, 52 initially treated) of 130 patients. The proportion of eyes with at least a 5-letter VA loss at 24 months was not significantly different between the groups: 65% with initial observation and 42% with initial treatment (p = 0.39). However, initially observed eyes were more likely to have a 10-letter VA loss at 24 months (OR = 4.6, p = 0.022). Most of eyes in the initial observation group received at least one treatment (an intravitreal injection in 66% and macular laser in 20%) during the 24-month period. CONCLUSIONS: The risk of 5 letters loss was similar between both management groups. However, initially observed eyes were more at risk of developing moderate visual loss and more than 80% of them required treatment over 24 months.