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Background: High compliance is crucial for the success of a mass drug administration program to achieve lymphatic filariasis elimination. However, the presence of persistently noncompliant individuals might delay the elimination target. Besides, although context-based research is essential to designing effective strategies, only a few studies have focused on identifying factors that play a role in noncompliance with mass drug administration in Africa. Therefore, this study was conducted to identify the factors associated with noncompliance to prevent mass drug administration using ivermectin-with-albendazole for the elimination of lymphatic filariasis in Northwest Ethiopia., Methods: A case-control study was conducted in Jawi District, Northwest Ethiopia. All individuals who are permanently living in the study area and registered on the annual chemotherapy registration book since 2015 were included in this study. A two-proportion formula was used to estimate the required sample size and 348 cases and 348 controls were selected by identification number on the village chemotherapy registration book using a systematic sampling technique. Data were collected by face-to-face interviews using a structured questionnaire developed through an intensive literature review. Then, data were entered and cleaned by using the EPI DATA software, and analyses were conducted using SPSS version 26. Finally, a logistic regression analysis technique was applied to identify the risk factors using adjusted odds ratio as measures of effect., Results: A total of 690 (99.1%) participants, 345 cases and 345 controls, were included in the study. Younger age (AOR = 1.60; 95%CI: 1.10, 2.33), female sex (AOR = 1.56; 95%CI: 1.24, 3.93), thought of not being susceptible to the disease (AOR = 2.36, 95%CI: 1.80, 4.32), lack of disease knowledge (AOR = 1.88; 95% CI: 1.38, 3.81), fear of drug side effect (AOR = 2.45; 95% CI:1.23, 4.86), and not participating in community drug distributors selection (AOR = 2.58; 95% CI: 1.70, 3.91) were found to be the risk factors significantly associated with noncompliance., Conclusion: Noncompliance with lymphatic filariasis mass drug administration therapy was associated with specific demographic, individual, program, and drug delivery characteristics. This finding has important implications for program effectiveness and would be used to accelerate the elimination of lymphatic filariasis in the study area and other endemic settings., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Fetene Mihretu et al.)