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Background: Little is known about depressive symptoms in podoconiosis despite the independent contribution of depression to worse health outcomes and disability in people with other chronic disorders. Method: Two-hundred and seventy-one individuals with podoconiosis and 268 healthy neighbours (individuals from the nearest household in any direction) were investigated for depressive symptoms using a validated Amharic version of the Patient Health Questionnaire (PHQ-9). The WHO Disability Assessment Schedule II (WHODAS II) tool was used to measure disability. Logistic regression and zero inflated negative binomial regression were used to identify factors associated with elevated depressive symptoms, and disability, respectively. Results: Among study participants with podoconiosis, 12.6% (34/269) had high levels of depressive symptoms (scoring 5 or more points on the PHQ-9, on two assessments two weeks apart) compared to 0.7% (2/268) of healthy neighbours (p<0.001). Having podoconiosis and being older were significantly associated with increased odds of a high PHQ-9 score (adjusted odds ratios [AOR] 11.42; 95% CI 2.44-53.44 and AOR 1.04; 95% CI 1.00- 1.08, respectively). Significant predictors of a higher disability score were having podoconiosis (WHODAS II multiplier value: 1.48; 95% CI 1.39-1.58) and having a high PHQ-9 score (1.07; 95% CI 1.06-1.08). Conclusion: We recommend integrating evidence-based treatments for depression into podoconiosis interventions. [ABSTRACT FROM AUTHOR]