Background: Volatile organic compounds (VOCs) are a large group of chemicals widely used in people's daily routines. Increasing evidence revealed the VOCs' accumulating toxicity. However, the VOCs toxicity in male prostate has not been reported previously. Thus, we comprehensively evaluated the association between VOCs and prostate-specific antigen (PSA).Methods: A total of 2016 subjects were included in our study from the National Health and Nutrition Examination Survey with VOCs, PSA, and other variables among U.S. average population. We constructed XGBoost Algorithm Model, Regression Model, and Generalized linear Model (GAM) to analyze the potential association. Stratified analysis was used to identify high-risk populations.Results: XGBoost Algorithm model identified blood chloroform as the most critical variable in the PSA concentration. Regression analysis suggested that blood chloroform was a positive association with PSA, which showed that environmental chloroform exposure is an independent risk factor that may cause prostate gland changes [β, (95% CI),P= 0.007, (0.003, 0.011), 0.00019]. GAM observed the linear relationship between blood chloroform and PSA concentration. Meanwhile, blood chloroform linear correlated with water chloroform in the lower dose range, indicating that the absorption of water may be the primary origin of chloroform. Stratified associations analysis identified the high-risk group on the chloroform exposures.Conclusion: This study revealed that blood chloroform was positively and independently associated with total PSA level, suggesting that long-term environmental chloroform exposure may cause changes in the prostate gland.