Abstract: Introduction: Leprosy is a chronic disease that attacks the peripheral nerves, skin and other body tissues. A leprosy reaction is an acute episode in which leprosy occurs as a result of sudden changes in the immune system. Leprosy reactions can occur before, during, and after treatment. In type I leprosy reactions, it is very important to recognize and treat appropriately, otherwise there can be rapid and extensive nerve damage while in mild type II reactions, it can disappear immediately but severe type II reactions can persist for years. Aim: The purpose of this study was to determine and analyze the influence of the determinant factors of leprosy reactions based on Biological, and Psychological reactions in leprosy patients at Naob Hospital, TTU Regency. Material and Methods: This type of research is analytic survey research with cross sectional design. The population in this study was people with leprosy who experienced reactions of leprosy types I and II with a total of 65 people with leprosy. This study uses a total sampling technique, namely sampling in which the number of samples is the same as the population which is 65 people. The data analysis included univariate and bivariate with chi-square test and multivariate with logistic regression test. Results: The results showed that there was a relationship between biological reactions (Type of Leprosy, Duration of Illness and Disability), and there was a significant relationship between psychological reactions (Stress) with the incidence of leprosy reactions in the patients at Naob Hospital, TTU Regency with p-value<α (0.05). Simultaneously, the independent variable (Type of Leprosy, Duration of Illness, Disability and Stress) had an effect of 55% on the dependent variable (Leprosy Reaction) in leprosy patients at Naob Hospital, TTU Regency. The most influential independent variable is duration of illness.