Leprosy is a disease problem in Indonesia, ranked third with the highest number of cases in the world, a complex condition involving physical health and quality of life of patients. Quality of life is closely related to knowledge, family support and stigma, where these factors can affect the quality of life. The purpose of this study was to analyze the relationship between knowledge, family support and stigma with the quality of life of people with leprosy in Lima Puluh Kota District. This research is an observational study, using a cross sectional research design. The study population was 45 people so that the research sample was taken by total sampling, that is, all populations were used as research samples. Data collection used secondary data in the form of a list of leprosy patients and primary data was obtained by means of a questionnaire. The data analysis method includes univariate analysis and bivariate analysis using simple logistic regression tests. The analysis showed that knowledge (p <0.001), family support (p = 0.024) and stigma (p = 0.034) had a significant relationship with the quality of life of people with leprosy in Lima Puluh Regency. Efforts to increase knowledge by providing IEC (communication, information and education), providing motivation and full support in carrying out medication, self-care so that the quality of life of people with leprosy will be better.