Summary Introduction: In addition to multi-drug treatment, patient self-care practice is crucial for the successful treatment of the disease. This study assessed the knowledge and self-care practices of leprosy patients at ALERT leprosy referral hospital in Ethiopia. Methods: A total of 424 leprosy patients were interviewed using pre-tested structured questionnaires. The questionnaires included core points such as sociodemographic characteristics, knowledge of leprosy and self-care practices. Bloom’s cut off point was used to describe the knowledge and self-care practices of the respondents and statistical significance was assessed at 95% confidence interval with 5% of level of significance. Results: The knowledge score of the respondents was poor for 276 (65·1%) and good for 148 (34·9%). The level of knowledge varied significantly with respect to age group (p , 0·01), sex (p , 0·01), marital status (p ¼ 0·003), educational status (p , 0·01) and income (p , 0·01). About 77·4% of interviewed patients had poor self-care practices and only 22·6 of patients had a good self-care practice score (p , 0·01). Age (p ¼ 0·002), previous disability due to leprosy (p , 0·01), knowledge of leprosy (p ¼ 0·038) and income (P ¼ 0·028), were significantly associated with poor selfcare practice. Conclusion: Although leprosy treatment, disability prevention and rehabilitation programs have been run in the country for decades, poor leprosy self-care practice and poor leprosy knowledge has been confirmed in this study. Therefore, the leprosy program should re-visit its strategy and mode of delivery to improve the leprosy knowledge and leprosy self-care practices of patients.