Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly. Genetic mechanisms underlying AMD are complex. Understanding the etiology of AMD is important because of the significant health and social concerns. In this paper, we describe a forest-based approach to systematically identifying multiple genes, gene-gene interactions and gene-environment interactions underlying complex diseases in genomewide case-control studies and the application of this approach to a published data set on AMD. Our analysis not only confirmed two known haplotypes, ACTCCG (on chromosome 1 with a p-value of 1.98e-6) and TCTGGACGACA (on chromosome 7 with a p-value of 9.81e-3), but also revealed two novel haplotypes, GATAGT (on chromosome 5 with a p-value of 3.46e-3) and TCTTACGTAGA (on chromosome 12 with a p-value of 3.16e-2). Thus, the significance of this work is twofold. First, we propose a powerful and robust method to identify high-risk haplotypes and their interactions; second, we reveal potential genetic variants associated with AMD.