Abstract Body: Volatile organic compounds (VOCs) are ubiquitous gaseous chemicals present in indoor and outdoor air. These compounds are emitted from several sources such as automobiles, paints, and household items. Human exposures are frequent and expected to increase with climate change. VOC exposures have been linked to negative cardiometabolic effects; however, the underlying mechanisms by which they impact cardiovascular function remain unknown. Exposure to VOCs may stimulate sympathetic nervous system activity. Thus, we aim to investigate the association of urinary VOC metabolites with levels of catecholamines as a biomarker of sympathetic activation. Participants (n=806, age 25-70) were recruited between 2018-2021 from low- to middle-income neighborhoods in Louisville, KY. Clean catch, spot urine samples were obtained during an in-person study visit. Urinary samples were used to quantify metabolites of VOCs and catecholamines using UPLC-MS/MS. The associations of log-transformed, creatinine standardized urinary constituents were examined using adjusted multivariable linear regression models for individual metabolites and quantile-based g computation for overall mixture models. Final models were adjusted for relevant demographic factors, stress, smoking status, medication use, and urine collection time. Detectable levels of acrylamide, acrolein, 1,3-butadiene, crotonaldehyde, N, N-dimethylformamide, propylene oxide, styrene, toluene, and xylene metabolites were present in >80% of urinary samples. In adjusted models, higher concentrations of most VOC metabolites, other than BMA (a metabolite of toluene), were associated with higher levels of urinary catecholamines (p<0.001). Specifically, a 10% increase in 11 individual VOC metabolites was associated with 1.2% to 2.4% higher epinephrine, 0.7% to 1.4% higher norepinephrine, and 0.7% to 1.5% higher dopamine levels. A quartile increase in the overall VOC metabolite mixture was associated with 57% higher epinephrine (95%CI = 41, 76%; p<0.001), 37% higher norepinephrine (95%CI=28, 48%; p<0.001), and 40% dopamine levels (95%CI=31, 48%; p<0.001). Our results suggest that exposure to these ubiquitous volatile compounds is associated with an increase in sympathetic stimulation. Mixture analysis further demonstrated potential additive effects of VOC exposures on autonomic modulation. Hence, an elevated sympathetic tone may in part be responsible for the negative cardiometabolic outcomes related to increased VOC exposure.