Leptin, a 167-amino acid protein secreted by adipocytes, has been shown to reduce beta-amyloid deposition and intracellular lipid concentration in animal models, two key pathogenic mechanisms underlying aging. We examined the association between serum leptin levels and AMD. We conducted a population-based case-control study including Chinese and Indian adults aged 40 to 80 years who participated in the Singapore Epidemiology of Eye Diseases Study (2007-2011). Age-related macular degeneration was assessed from retinal photographs graded using a modified Wisconsin Age-Related Maculopathy Grading System (n = 426; early = 389, late = 37). Controls (n = 927) without AMD were frequency matched for age, sex, and ethnicity. Serum leptin levels were measured using direct sandwich ELISA. Participants with AMD had lower levels of leptin compared with those without (mean [SD] = 10.0 [11.5] ng/mL versus 12.9 [16.4] ng/mL; P = 0.001). Mean levels of leptin among those with late, early, and without AMD were 8.8, 10.1, and 12.9 ng/mL (P trend = 0.005). In multivariable models adjusting for potential confounders, including smoking, body mass index, blood pressure, and high-density lipoprotein cholesterol, increasing quartiles of leptin were associated with lower odds of AMD, odds ratio (95% confidence interval) of AMD was 0.56 (0.34-0.92) comparing highest to lowest quartile of serum leptin. In subgroup analyses, the inverse association between leptin and AMD was significant in women, Indian ethnicity, and ex-smokers. Higher serum leptin levels were inversely associated with AMD. These findings, if confirmed in prospective studies, may provide insights into new pathogenic pathways and possibly therapeutic targets in AMD.