Objective: To understand the economic burden caused by hand-foot-mouth disease (HFMD) in Xi’an, in order to provide scientific basis for government departments to allocate health resources rationally. Methods: New cases of HFMD were selected randomly from designated hospitals in city and district level in Xi’an, 2018, Direct and indirect economic costs of patients caused by HFMD were collected using a questionnaire survey, hospital charging system inquiry as well as follow-up survey. Factors affecting the economic burden of HFMD were analyzed. Results: A total of 438 mild as well as 60 severe cases were surveyed, with the overall medical insurance participation rate of 89.76%(447/498). The median of per capita direct economic burden of mild and severe cases were 635 and 7 972 yuan respectively, and the median of per capita indirect economic burden of mild and severe cases were 130 and 233 yuan respectively, in Xi’an. The overall economic burden attributable to HFMD was 23.1 million yuan in Xi’an 2018, in which the direct economic burden was 19.3 million yuan, indirect economic burden was 3.8 million yuan. Multiple Logistic regression analysis showed that the approach of diagnosis, type of cases, days of treatment and type of pathogen had significant influence on the economic burden of HFMD(P<0.05). Conclusion The economic burden of HFMD was heavy in Xi’an. Controling and reducing the incidence rate, as well as increasing the medical insurance coverage and reimbursement rate would lighten the economic burden caused by HFMD effectively.