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Background A lot of time and money was needed during the diagnosis and treatment process of leprosy, the delayed leprosy would also impair the labor capability of patients as well, and these put a heavy burden for the leprosy patients. The migrant leprosy patient is a special group and need more concern. Our goal was to assess the economic burden of leprosy on migrant and resident patient populations in Guangdong province, China. Methods We conducted a population-based cross-sectional survey from February to July of 2016. A self-designed questionnaire was administered to leprosy patients who: (1) had registered in Leprosy Management Information System in China (LEPMIS) by the end of February 2016, (2) had received multiple drug treatment (MDT) drugs at a local leprosy control institution for three consecutive months or had had at least one physical check in the past half year, and (3) were willing to take part in the investigation and give informed written consent. Demographic characteristics, Financial and disease information, and costs before and after leprosy diagnosis were collected and compared using t-test and χ2 test. Results A total of 254 participants completed the questionnaires, including 168 males and 86 females. Migrants and residents accounted for 33.9% and 66.1% of patients, respectively. Among migrant patients, the median cost before diagnosis was $131.6 (39.2–450.9), the median yearly cost of leprosy treatment after diagnosis was $300.6 (158.4–868.5), and the median yearly cost of leprosy complications was $69.5 (11–178.4). In comparison, among residents the median yearly costs were $152.4 (30.7–770.9) pre-diagnosis, $309.7 (103.2–1016.7) after diagnosis, and $91.9 (32.6–303.1) for leprosy complications. Base on this, we determined that the median yearly total expense after diagnosis amounted to 15% of migrant and 38% of resident patients’ annual income. Conclusion Leprosy places a heavy economic burden on both migrant and resident leprosy patients and governmental policies and programs could substantially alleviate this. Measures to implement more active surveillance and early diagnosis would benefit both populations, while labor protection and medical insurance are urgently needed for migrant patients and easier access to medical services and social aids could substantially decrease the burden of leprosy for resident patients.