OBJECTIVES The objective was to characterise and identify potential risk factors for intolerance to multi-drug leprosy therapy (MDT) which prompted a medication change in a leprosy referral centre in northeastern Brazil. DESIGN A retrospective chart review of leprosy patients treated at a state referral centre for leprosy in Natal, Rio Grande do Norte, Brazil was completed. Chart review focus was on adverse effects necessitating modification of MDT regimen. RESULTS Six hundred and twelve records were reviewed with detection of 91 (14.8%) adverse effects with associated change in MDT regimen. The most common recorded causes of medication intolerance were anemia (8.7%), headache (4.2%), cyanosis (1.8%), and gastrointestinal symptoms (1-6%). Both female gender (OR = 2.63) and age less than 42 years old (OR = 2.7) remained risk factors for MDT intolerance in a multivariate model including gender, age, and WHO regimen type. With intolerance due to anemia as the outcome, female gender (OR = 2.36) and age less than 42 years (OR = 1.86) were associated. CONCLUSIONS In this study, female gender and younger age were associated with greater risk of medication intolerance and medication intolerance related to anemia. These findings have important operational implications for drug intolerance monitoring during therapy for leprosy.