To date there is no accepted clinical diagnostic test for Parkinson's disease (PD) based on biochemical analysis of blood or cerebrospinal fluid (CSF). α‐Synuclein (α‐syn) protein has been linked to the pathogenesis of PD with the discovery of mutations in the gene encoding α‐syn in familial cases with early‐onset PD. Lewy bodies and Lewy neurites, which constitute the main pathological features in the brains of patients with sporadic PD and dementia with Lewy bodies, are formed by the conversion of soluble monomers of α‐syn into insoluble aggregates. We recently reported the presence of α‐syn in normal human blood plasma and in postmortem CSF. Here, we investigated whether α‐syn can be used as a biomarker for PD. We have developed a novel ELISA method that detects only oligomeric “soluble aggregates” of α‐syn. Using this ELISA, we report the presence of significantly elevated (P=0.002) levels of oligomeric forms of α‐syn in plasma samples obtained from 34 PD patients compared with 27 controls; 52% (95% confidence intervals 0.353–0.687) of the PD patients displayed signals >0.5 OD with our ELISA assay in comparison to only 14.8% (95% confidence intervals 0.014 –0.281) for the control cases. An analysis of the test's diagnostic value revealed a specificity of 0.852 (95% confidence intervals 0.662– 0.958), sensitivity of 0.529 (95% confidence intervals 0.351–0.702) and a positive predictive value of 0.818 (95% confidence intervals 0.597–0.948). These observations offer new opportunities for developing diagnostic tests for PD and related diseases and for testing therapeutic agents aimed at preventing or reversing the aggregation of α‐syn.—El‐Agnaf, O. M. A., Salem, S. A., Paleologou, K. W., Curran, M. D., Gibson, M. J., Court, J. A., Schlossmacher, M. G., Allsop, D. Detection of oligomeric forms of α‐synuclein protein in human plasma as a potential biomarker for Parkinson's disease. FASEB J. 20, 419 –425 (2006)