PURPOSE. Pseudoexfoliation (PEX) syndrome is a generalized elastic microfibrillopathy characterized by fibrillar deposits in intra- and extraocular tissues. Genetic and nongenetic factors are known to be involved in its etiopathogenesis. This study was focused on six functional candidate genes involved in PEX material deposition and the analysis of their potential association with PEX syndrome and PEX glaucoma (PEXG). METHODS. Fifty single-nucleotide polymorphisms (SNPs) capturing > 95% of overall genetic variance observed in Europeans at loci for FBN1, LTBP2, MFAP2, TGM2, TGF-b1, and CLU were genotyped in 333 unrelated PEX-affected and 342 healthy individuals of German origin, and a genetic association study was performed. To replicate the findings, two SNPs of the CLU gene were genotyped in a further 328 unrelated German patients with PEX as well as in 209 Italian patients with PEX and 190 Italian control subjects. RESULTS. Association with PEX was observed only for the SNP rs2279590 in intron 8 of the CLU gene coding for clusterin (corrected P = 0.0347, OR = 1.34) in our first German cohort. Likewise, a frequent haplotype encompassing the associated risk allele showed nominally significant association. None of remaining SNPs or SNP haplotypes were associated with PEX. The association found was confirmed in a second German cohort (P = 0.0244) but not in the Italian cohort (P = 0.7173). In addition, the association with CLU SNP rs2279590 was more significant in German patients with PEX syndrome than in those with PEXG. CONCLUSIONS. Genetic variants in the gene encoding clusterin may represent a risk factor for PEX in German patients but not in Italian patients. Variants in FBN1, LTBP2, MFAP2, TGF-b1, and TGM2 do not play a major role in the etiology of PEX syndrome, at least in German patients. (Invest Ophthalmol Vis Sci. 2009; 50: 2796-2801) DOI: 10.1167/iovs.08-2339