BACKGROUND: Previous studies of age-related macular degeneration have not quantified the number of drusen that accumulate fluorescein. Histopathologic studies have demonstrated druse subregions with different degrees of hydrophobicity, and these subregions might potentially exhibit different degrees of fluorescein uptake. METHODS: We evaluated macular drusen from 35 age-related macular degeneration patients by measuring druse area in color digital images and fluorescein angiograms, using 2 morphometric methods. RESULTS: Of 828 drusen evaluated, 405 had a corresponding fluorescein angiogram signal. About half of all drusen per eye (49.57%) stained in each participant. Among fluorescein-stained drusen, druse size measured in color images did not differ significantly from the sizes measured in corresponding fluorescein images (P = 0.8105), across the range of druse sizes. CONCLUSION: These findings indicate that our understanding of drusen subregion staining may not directly correlate to in vivo observations of macular drusen in age-related macular degeneration.