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Background: To eliminate blinding trachoma, the World Health Organization emphasizes implementing the SAFE strategy, which includes annual mass drug administration (MDA) with azithromycin to the whole population of endemic districts. Prevalence surveys to assess impact at the district level are recommended after at least 3 years of intervention. The decision to stop MDA is based on a prevalence of trachomatous inflammation follicular (TF) among children aged 1–9 years below 5% at the sub-district level, as determined by an additional round of surveys limited within districts where TF prevalence is below 10%. We conducted impact surveys powered to estimate prevalence simultaneously at the sub-district and district in two zones of Amhara, Ethiopia to determine whether MDA could be stopped. Methodology: Seventy-two separate population-based, sub-district surveys were conducted in 25 districts. In each survey all residents from 10 randomly selected clusters were screened for clinical signs of trachoma. Data were weighted according to selection probabilities and adjusted for correlation due to clustering. Principal Findings: Overall, 89,735 residents were registered from 21,327 households of whom 72,452 people (80.7%) were examined. The prevalence of TF in children aged 1–9 years was below 5% in six sub-districts and two districts. Sub-district level prevalence of TF in children aged 1–9 years ranged from 0.9–76.9% and district-level from 0.9–67.0%. In only one district was the prevalence of trichiasis below 0.1%. Conclusions/Significance: The experience from these zones in Ethiopia demonstrates that impact assessments designed to give a prevalence estimate of TF at sub-district level are possible, although the scale of the work was challenging. Given the assessed district-level prevalence of TF, sub-district-level surveys would have been warranted in only five districts. Interpretation was not as simple as stopping MDA in sub-districts below 5% given programmatic challenges of exempting sub-districts from a highly regarded program and the proximity of hyper-endemic sub-districts. Author Summary: Trachoma, the leading cause of preventable blindness, is targeted for "elimination as a public health problem" by the year 2020. National programs are implementing the recommended strategy of surgery, antibiotics, facial cleanliness, and environmental improvements (SAFE) to meet this target. Many programs are currently facing the decision of when to scale down interventions, particularly mass drug administration (MDA) of azithromycin. We implemented large population-based surveys in two different zones of the Amhara National Regional State of Ethiopia. Rather than conducting an impact assessment first at the district level, followed by additional sub-district-level surveys, we took a novel approach to measure the prevalence of trachoma at sub-district level to be able to make an immediate decision of whether to stop MDA. Over 72,000 people in 714 communities in 72 sub-districts were examined for clinical signs of trachoma. We identified only six sub-districts that met criteria for being able to stop MDA. Our work demonstrates that determining the prevalence of trachoma at sub-district level is feasible but requires significant resources. In this hyper-endemic setting, sub-district-level surveys were not needed in the majority of districts. Overall, the clinical data suggest some decline in trachoma within these areas since the SAFE strategy was implemented. [ABSTRACT FROM AUTHOR]