Humoral immune responses were studied in 118 Venezuelan patients with either active mucocutaneous (MCL) or localized cutaneous leishmaniasis (LCL). Most patients had elevated antibody levels to the six promastigote oligosaccharide residues studied: galactosyl(α1–2)galactose, galactosyl(α1–3)galactose, galactosyl(α1–6)galactose, galactosyl(α1–3)mannose, galactofuranosyl(β1–3)mannose, and galactocerebroside. Significantly higher antibody levels were found in patients with MCL against galactosyl(α1–3)galactose and Leishmania tropica glycoinositol phospholipid (GIPL)-1, GIPL-2, and GIPL-3 compared with patients with LCL. For both clinical forms of American cutaneous leishmaniasis (ACL), the most reactive antigen was galactosyl(α1–3)galactose, with elevated levels found in 63% and 79% of MCL and LCL patients, respectively. In patients with MCL and LCL, no significant relationship was found between antibody levels against a given oligosaccharide residue and clinical parameters such as age, leishmanin diameter, number of skin lesions, or time of evolution. It is noteworthy that 33% and 15% of MCL and LCL patients, respectively, did not have elevated antibody levels against the six different oligosaccharide residues studied. This suggests the presence of a subpopulation of nonhumoral immunoreactive ACL patients. The relationship between abnormal levels of oligosaccharide antibodies and the final outcome of the disease remains to be established.