Abstract Histiocytic sarcoma (HS) is a cancer characterized by unregulated proliferation of histiocytes. In the flat-coated retriever (FCR), the primary tumor site is frequently appendicular with a high rate of local and distant metastases. The disease occurs with a high prevalence in the FCR, accounting for approximately 40% of all cancers in the breed and 18% of disease-related deaths in a UK cohort. Breed-specific prevalence in FCRs indicates a strong genetic predisposition. Our goal is to identify the underlying loci and causal mutations associated with HS in the FCR. A whole genome association study (GWAS) using the Illumina Canine SNP20 BeadChip was performed using 98 DNA samples from FCR collected from the United States (48 cases and 50 unaffected controls over the age of ten yrs). Of the 23,000 SNPs genotyped, 17,000 were informative in the FCR. A single-marker chi-squared analysis using EMMA to correct for population structure and kinship yielded an association with the HS phenotype (p=2.33×10-5). Including the flanking markers, the associated region spans 12 Mb and includes several candidate genes of interest. To reduce this critical interval, ABI SNPlex genotyping and candidate gene sequencing is in progress. Our current data distinguish HS in the FCR from the related disease malignant histiocytosis (MH) found in Bernese mountain dogs (BMD). MH is a disseminated histiocytic cancer with primary tumor sites usually occurring in visceral organs. Our data suggest that HS in the FCR is not a localized form of MH. GWAS analyses for both breeds indicate that the major contributing heritable factors of MH in the BMD differ from those for HS in the FCR. Given the different behaviors of the cancers between the two breeds and the different heritable loci associated with them, our current evidence distinguishes them as separate diseases. Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4745.