Objective: To determine the histidine frequency in patients with the cuticular drusen phenotype of age-related macular degeneration (AMD)., Methods: Fifty individuals were identified who met the criteria for the cuticular drusen phenotype using a standard threshold photograph. We genotyped DNA samples using a polymerase chain reaction-based restriction digest assay. Seven hundred individuals with typical AMD and 252 controls were also genotyped. Fisher exact test was used to analyze the significance of allele frequency differences., Results: The histidine variant was present in 70% (frequency +/- SE, 0.70 +/- 0.05) of the cuticular cohort, 55% (frequency +/- SE, 0.55 +/- 0.01) of the more typical AMD cases, and 34% (frequency +/- SE, 0.34 +/- 0.02) of controls. The association between the cuticular drusen phenotype and the histidine allele was highly significant (P = .003; odds ratio, 2.0; 95% confidence interval, 1.21-3.07; vs AMD cases P<.001; odds ratio 4.54; 95% confidence interval, 2.79-7.50; vs controls). Genotype distribution between the 3 groups was similarly significant (P<.001)., Conclusion: The cuticular drusen phenotype is highly associated with the Tyr402His variant of the complement factor H (CFH) gene. The significantly higher histidine allele frequency in this group compared with the typical AMD cohort suggests that the complement cascade may play a greater role in the pathogenesis of the cuticular drusen subtype than in AMD as a whole., Clinical Relevance: The c.1204T>C, p.Tyr402His allelic variant in the CFH gene is associated with a 3-fold increased risk for AMD. A high frequency of the histidine allele has also been noted in patients with membranoproliferative glomerulonephritis type II.