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Background: Despite evidence from experimental studies linking some petroleum hydrocarbons to markers of immune suppression, limited epidemiologic research exists on this topic. Objective: The aim of this cross-sectional study was to examine associations of oil spill related chemicals (benzene, toluene, ethylbenzene, xylene, and n-hexane (BTEX-H)) and total hydrocarbons (THC) with immune-related illnesses as indicators of potential immune suppression. Methods: Subjects comprised 8601 Deepwater Horizon (DWH)oil spill clean-up and response workers who participated in a home visit (1–3 years after the DWHspill) in the Gulf Long-term Follow-up (GuLF) Study. Cumulative exposures to THC and individual BTEX-H constituents during the oil spill clean-up were estimated using a job-exposure matrix linking air measurement data to detailed participant work histories. Study outcomes included post-spill occurrence and/or frequency of illnesses ascertained at the home visit, including colds, flu, cold sores, pneumonia, and shingles. Frequent cold and frequent flu were defined as ≥4 colds and ≥2 episodes of flu since the spill, respectively. We examined an aggregate outcome of frequent colds, anyflu, cold sores, or pneumonia since the spill. In single pollutant models, we used multivariable log-binomial regression to estimate prevalence ratios (PR) and 95% confidence intervals (CI) for associations between quartiles of THC and BTEX-H exposures with each outcome. We used quantile g-computation to estimate the joint effect of the BTEX-H mixture. Results: We observed positive associations of increasing quartiles of THC and BTEX-H with all outcomes except shingles, with evidence of an exposure-response for most outcomes. Strongest associations were observed for frequent flu (range of PR: 1.41–1.67). The BTEX-H mixturewas associated with small to modest elevations in PRs for most outcomes. Impact Statement: This study is the first to our knowledge to demonstrate an association between oil spill BTEX-H exposures and multiple immune-related illnesses as measures of potential immune suppression. Increasing oil spill-related volatile hydrocarbon exposures may increase the risk of multiple immune-related illnesses, especially frequent cold and frequent flu. Future research on this topic using more robust measures of immune function would advance existing evidence on this relationship.