BACKGROUND: Podoconiosis is a non-filarial swelling of lower extremity endemic in tropical regions, North America and India. The etiology and pathophysiology of the disease remain unknown. The objective of this study was to identify the determinants of Podoconiosis. METHODS: Unmatched case control study design was conducted. The sample size was calculated using Epi-info soft ware: 95% CI, 85% power, control to case ratio of 2:1, expected frequency of barefoot among controls 50%, odds ratio of 1.5 and non-response rate of 10% yielding 1148 study participants. Binary logistic regression was used to identify the determinants of Podoconiosis. RESULTS: A total of 1113 study participants (379 cases and 734 controls) were included giving for a response rate of 96.95%. Positive family history (AOR, 2.81 [95% CI: 1.7-4.64]), bare foot (AOR, 3.26 [95% CI: 2.03-5.25]), poor foot hygiene (AOR, 2.68 [95 CI: 1.72 - 4.19]) increase the risk of Podoconiosis. Female gender (AOR, 0.26 [95% CI: 0.15-0.44]), good housing condition (AOR, 0.17 [95% CI: 0.1-0.3]), medium income (AOR, 0.12 [95 % CI: 0.07- 0.22]) and primary education (AOR, 0.02 [95% CI: 0.01-0.04]) decrease the risk of Podoconiosis. CONCLUSION: Podoconiosis control and prevention programmes should involve the low income and uneducated populations.  KEYWORDS: Podoconiosis, Determinants, Ethiopia