Abstract Background Chemical Intolerance (CI) is characterized by multi-system symptoms initiated by exposures to environmental toxins. Symptoms include fatigue, headache, mood changes, musculoskeletal pain, gastro-intestinal issues, difficulties with memory/concentration. With mixed results, researchers have used targeted genetic approaches to understand the genetic pathways associated with CI. This study is the first to apply a genome-wide untargeted exploratory approach. Methods A high-density genotyping platform was used to perform a hypothesis-free search for genetic variants associated with CI in a set of 200 participants. Each CI patient was verified using a validated survey. The association between CI and SNPs was obtained using SOLAR (Sequential Oligogenic Linkage Analysis Routines). Gene-Chemical-Disease interactions were determined using the DisGeNET Database. Results Several associated SNPs/genes were identified with either increased or decreased risk of CI. Four chemicals were found to alter gene expression (bisphenol A, valproic acid, aflatoxin B, and benzo(a)pyrene). There were common adverse health effects associated with the genes and the chemicals that influence them, including inflammation, gastrointestinal and immune system disorders, nervous system diseases, and intellectual disabilities. Discussion This study supports evidence of novel genetic components associated with CI that may interact with common ubiquitous chemical and drug exposures affecting gene expression. The identified health consequences are common to individuals with CI and implies gene/chemical exposure interactions that may influence the development or exacerbation of symptoms associated with CI. The identified chemicals affecting these genes are ubiquitous environmental toxins, entering the body through air, food, and water, suggesting the need for greater public health policy efforts.