To evaluate whether drusen of subjects with fibulin-5 mutation-associated age-related macular degeneration (AMD) have clinically demonstrable drusen domains as evidenced by differences between color and fluorescein angiographic profiles. Of seven patients we identified with AMD due to mutations in the fibulin-5 gene (Fib-5 AMD), five had color fundus photography and fluorescein angiography (FA). One had bilateral choroidal neovascularization and no drusen. For each eye, the green channel (GC) of the digital RGB (Red-Green-Blue) color image and hyperfluorescent domain (HD) intensity of the FA image were registered and drusen were manually segmented and measured. Totally 75 small (≤62 μm), 110 intermediate (63-125 μm), and 30 large (>125 μm) drusen were measured in four patients within the 6 × 6 mm central macular areas. All four subjects demonstrated central or paracentral HDs within each drusen perimeter. HDs were found in association with each druse, with a HD/GC ratio of 0.82, 0.76, and 0.72 respectively for small, intermediate, and large drusen (Student T Test: P < 0.01, P < 0.01, P < 0.01). A statistical difference was found for the HD/GC ratios between small- and intermediate-sized drusen and small- and large-sized drusen but not between intermediate-sized and large-sized drusen (P = 0.001, P < 0.001, P > 0.05, respectively). AMD patients with mutations in fibulin-5 share drusen phenotypic structure and have HD/GC ratios that are similar to individuals with cuticular or basal laminar drusen. Drusen substructure may reflect similarities in drusen stage and/or genesis and appear to vary among AMD genotypes.