Background: The objective of this analysis was to perform unbiased discovery of genetic variants that modulate neutropenia risk early in docetaxel treatment. Methods: Chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel and prednisone ± bevacizumab on the CALGB 90401 trial who experienced grade 3+ neutropenia (ANC < 1,000 cells/mm³) within the first two treatment cycles (cases) were compared with controls who completed two cycles without grade 3+ neutropenia. All single nucleotide polymorphisms (SNPs) genotyped on the Illumina HumanHap610-Quad platform that passed quality control were included in a genome-wide association study (GWAS) in genetically-defined European subjects. SNPs selected for future replication, based on p-value and biological relevance to neutropenia, were adjusted for treatment arm, age, baseline ANC, smoking status and palliative radiation. Results: The incidence of grade 3+ neutropenia within the first two cycles was 22.6% (172/761). 590 European subjects fulfilling the case or control criteria were evaluated in a discovery GWAS of 498,022 SNPs. The top hit was an intronic SNP (rs12431732) in ACTN1, which bundles actin in the neutrophil cytoskeleton. Actin specific antibodies have been detected in auto-immune neutropenia, providing a plausible biological mechanism. Ten SNPs, many in genes involved in leukocyte homeostasis such as SERPINA3 and BAALC, were prioritized for future replication (Table). Conclusions: GWAS in a prospectively enrolled mCRPC patient cohort identified SNPs that may influence risk of docetaxel-induced neutropenia, adjusted for bevacizumab treatment. Replication in independent cohorts of docetaxel treated patients is necessary to verify the influence of these SNPs on neutropenia risk.