Background Age-related maculopathy (ARM) or degeneration (ARMD) is the leading cause of irreversible blindness in developed countries. Despite several studies on the morphology of ARMD, the aetiology is unknown and factor(s) contributing to the pathogenesis remain to be characterised. More recent studies have demonstrated that cholesterol esters and lipids are present within Bruch's membrane deposits and drusen, and dietary fat intake is associated with ARMD. The product of Ob gene, leptin, is a recently discovered peptide participating in human metabolism. There is a direct relationship between serum leptin and diet, and lipoprotein metabolism, but the role of leptin in the course of ARMD has not previously been investigated. Purpose This cross-sectional case-control study investigated whether serum leptin level was associated with ARMD as a new possible risk factor and to assess its relationship with disease severity. Methods A total of 32 patients with ARM or ARMD (17 men, 15 women) and 20 age- and sex-matched healthy control subjects without ARMD (11 men, nine women) from a similar ethnic background were enrolled in this multicentre study. Body mass index (BMI) (weight (kg)/height (m(2))) was calculated for each group. The presence of maculopathy was assessed on the basis of colour fundus photographs using an international classification system. Patients were classified as early-ARM (n = 16) or late-ARMD (n = 16) using clinical examination and grading of photographs. Serum leptin levels were measured by an enzyme-linked immunosorbent assay kit. The Mann-Whitney U test or chi(2) test was used for statistics as indicated, and P<0.05 was considered to be significant. Results The age, sex ratio, and BMI between groups were comparable. Patients with maculopathy had significantly (P<0.001) lower leptin levels (mean +/- SD, 6.01 +/- 2.55 ng/ ml) than control subjects (13.21+/- 2.27 ng/ml). In addition, late-ARMD patients had significantly lower leptin levels (3.81 +/- 0.58 ng/ ml) than early-ARM patients (8.21 +/- 1.68 ng/ml, P<0.001) or control subjects (P<0.001). Conclusion Leptin seems to be a possible newly associated factor in the course of ARM and may be involved in the lipid composition of the macular lesions, especially in late-ARMD.