Buruli ulcer (BU) is a little understood severely debilitating skin disease caused by Mycobacterium ulcerans with serious health and economic consequences. It begins as a painless nodule, which if not treated early, results in serious injury, permanent disability, or even death. Few studies have assessed BU’s economic impact on its victims. We analyzed the economic burden of the disease on affected households in three endemic rural districts of Ghana. We used a 2003 household stratified survey to collect socioeconomic, demographic, and disease data from households affected by BU in Upper Denkyira (UD), Atwima (AT) and Amansie West (AW) districts in the Central and Ashanti regions of Ghana. We calculated the direct and indirect economic costs per case associated with BU by stage of disease and compared the costs of BU between and within substratum of the disease. Results for the 2003 data showed that a household with a BU case at the nodular stage incurred an annual cost of $34 (95% CI: $2-67), plaque or oedema stage incurred $304 (95% CI: $96.8-511), ulcer on the joint stage incurred $312 (95% CI: $189-435), ulcer not on the joint stage incurred $ 156 (95% CI: 11.4-302), a scar with visible contracture incurred $165 (95% CI: $69-262), while scar without a visible contracture incurred $163 (95% CI: 46-280). Buruli ulcer disease poses serious economic challenges to diseased households in rural Ghana. Early treatment for the disease is economical and should be promoted.