PURPOSE: To study associations of small, hard macular drusen and peripheral drusen with genotypes associated with age-related macular degeneration (AMD). METHODS: Digital grayscale fundus photographs recorded in red-free illumination were graded for the presence of drusen in 1107 subjects aged 30 to 66 years. Participants were genotyped for AMD-related polymorphisms in complement factor H (CFH), in LOC387715, and in complement factor B (CFB). RESULTS: The prevalence of 20 or more small, hard macular drusen per eye was 14%, with no association to the investigated polymorphisms. Peripheral drusen were associated with CFHY402H (odds ratio [OR], 4.3; 95% confidence interval [95% CI], 1.4-13, for CC versus TT genotypes) as was macular drusen >63 microm (OR, 1.9; 95% CI, 1.1-3.1, for CC versus TT genotypes). Macular drusen >63 microm were associated with the presence of 20 or more small, hard macular drusen (OR, 1.7; 95% CI, 1.1-2.6) and with peripheral drusen (OR, 2.5; 95% CI,1.2-5.4) CONCLUSIONS: In this study, the presence of 20 or more small, hard macular drusen per eye was not associated with known AMD-related polymorphisms, whereas the study confirmed an association of peripheral drusen with CFHY402H. (ClinicalTrials.gov number, NCT00289237).