Genetic variability in the promoter and 3′ region of the SNCA gene coding α‐synuclein modulates the risk to develop sporadic Parkinson's disease (PD). Whether this is mediated by regulating a‐synuclein expression levels remains unknown. Therefore, we analyzed levels of α‐synuclein in blood and human post mortem brain tissue including the substantia nigra using quantitative real‐time reverse transcriptase‐ polymerase chain reaction and enzyme linked immu‐nosorbent assay in vivo. Single nucleotide polymor‐phism (SNP) rs356219, a tagging SNP for a disease‐ associated haplotype in the 3′ region of the SNCA gene, has a significant effect on SNCA mRNA levels in the substantia nigra and the cerebellum. Further, the “protective” genotype 259/259 of the PD‐associated promoter repeat NACP‐Repl is associated with lower protein levels in blood than genotypes 261/261, 259/261, and 259/263. In conclusion, we provide evidence that a‐synuclein levels are influenced by genetic variability in the promoter and 3′ region of the SNCA gene in vivo.—Fuchs, J., Tichopad, A., Golub, Y., Munz, M., Schweitzer, K. J., Wolf, B., Berg, D., Mueller, J. C., Gasser, T. Genetic variability in the SNCA gene influences α‐synuclein levels in the blood and brain. FASEB J. 22, 1327–1334 (2008)