To date, the etiology of multiple system atrophy (MSA) has proved impenetrable. We investigated the role of genetic variation in the UCHL-1 gene in MSA and looked for the presence of disease susceptibility alleles. We determined the linkage disequilibrium structure of the gene and employed a haplotype tagging strategy with power to represent 95% of the haplotype diversity. This approach was performed using a set of tagging single nucleotide polymorphisms (SNPs) that can infer the allelic state of all the common SNPs in UCHL-1 with a high coefficient of determination. This strategy enabled us to scan across the gene and maintain the power to detect signal(s) from any potential functional variant(s). In 257 Gilman-probable or -definite MSA subjects and 1,536 controls, we did not detect a case-control frequency difference for either the tagged haplotypes or for individual tagging SNPs. This search included the S18Y variant of UCHL-1, which has been reported to be protective in Parkinson's disease. (c) 2005 Movement Disorder Society.