Antibodies to the species-specific phenolic glycolipid (PGL-1) of Mycobacterium leprae and a crude M. leprae sonicate were measured by ELISA in sera from newly diagnosed and treated leprosy patients from Sydney and Nepal. IgM anti-PGL-1 antibodies were present in 88-90% of untreated patients at the lepromatous pole of the clinical spectrum and 35-55% of those at the tuberculoid pole. In treated patients with either form of the disease, IgM anti-PGL-1 antibodies were within the normal range or minimally elevated. In contrast, high levels of IgG anti-PGL-1 antibodies were detected in both treated and untreated patients. Neither IgM nor IgG anti-PGL-1 antibodies were elevated in sera from Mantoux negative controls and only one out of 15 sera from patients with untreated tuberculosis contained significant amounts of antibody. Comparison of the data from the anti-PGL-1 assay with the antibody response to a crude M. leprae sonicate revealed that the latter assay yielded more variable results and discriminated less well between lepromatous and tuberculoid subjects and between untreated patients and those on therapy. Thus the IgM anti-PGL-1 response signifies the presence of active disease, particularly in multi-bacillary cases, and has the potential to be used not only to monitor the response of these patients to therapy, but also to detect subclinical leprosy in high-risk groups such as the relatives of patients with lepromatous disease.