According to increasing evidence, high‑density lipoproteins (HDLs) may raise prostate‑specific antigen (PSA) levels in the prostate. The link between HDL‑cholesterol (C) and PSA, on the other hand, is debatable and challenging. Hence, the present study examined the relationship between HDL‑C and PSA in men using the National Health and Nutrition Examination Survey (NHANES) database. NHANES data were extracted for five cycles from 2001 to 2010. The data used for analysis included PSA concentrations, sociodemographic and laboratory data. After the screening, 6,669 out of 52,195 participants were included in the present study. Participants were divided into four groups based on HDL‑C quartiles. Categorical and continuous variables using weighted chi‑square tests and linear regression models were analysed to compare differences between groups. A total of three weighted multivariate linear regression models were constructed and the association between HDL‑C and PSA using a smoothed curve fit was assessed. In the present study, unadjusted and adjusted multivariate linear regression models revealed a significant positive association between PSA concentrations and serum HDL‑C levels. Specifically, each unit increase in HDL‑C ratio was associated with an increase in PSA concentration by 0.470 ng/ml (P<0.001) in the unadjusted model. In minimally adjusted models, accounting for socioeconomic and demographic factors, this association remained significant, with an increase of 0.408 ng/ml per unit increase in serum HDL‑C (P<0.001). Furthermore, the stratified analysis revealed various impacts based on socioeconomic status and HDL‑C levels, with a significant interaction between household income and HDL‑C levels (P=0.037). Exclusion of subjects with low HDL‑C levels strengthened the association, revealing a significant increase in PSA concentration with higher HDL‑C levels (0.50 ng/ml per 1 mmol/l increase, P=0.009). The findings of the present study suggest a nuanced relationship between HDL‑C levels, socioeconomic factors, and PSA concentrations, highlighting the potential importance of considering these factors in prostate cancer (Pca) screening and risk assessment. The present study found a positive association between serum HDL‑C and PSA concentrations in adult men in the United States without a Pca diagnosis.

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