Buruli ulcer (BU) is an emerging necrotic skin disease caused by Mycobacterium ulcerans. To assess the potential for a serodiagnostic test, we measured the humoral immune response of BU patients to M. ulcerans antigens and compared this response with delayed-type hypersensitivity responses to both Burulin and PPD. The delayed-type hypersensitivity response generally supported the diagnosis of BU, with overall reactivity to Burulin in 28 (71.8%) of 39 patients tested, compared with 3 (14%) of 21 healthy controls. However, this positive skin test response was observed primarily in patients with healed or active disease, and rarely in patients with early disease (p=0.009). When tested for a serologic response to M. ulcerans culture filtrate, 43 (70.5%) of 61 BU patients had antibodies to these antigens, compared with 10 (37.0%) of 27 controls and 4 (30. 8%) of 13 tuberculosis patients. There was no correlation between disease stage and the onset of this serum antibody response. Our findings suggest that serologic testing may be useful in the diagnosis and surveillance of BU.