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Purpose: Current research has not extensively explored the correlation between Systemic Inflammatory Index (SII) and prostate-specific antibody (PSA) levels. This study aimed to investigate the relationship between the SII and PSA levels in American males aged > 40 years without prostate cancer. Methods: Data were obtained from the 2003–2010 National Health and Nutrition Examination Survey (NHANES). Patients without complete SII or PSA data were excluded. Multiple linear regression models were used to investigate the possibility of a linear association between the SII and PSA levels. Fitted smoothed curves and threshold effect analyses were used to characterize the nonlinear relationships. Results: The study included 5982 male participants over the age of 40 years from the United States. The average SII (mean ± standard deviation) was 562.78 ± 355.60. The mean value of PSA was 1.85 ± 3.24. The results showed that SII exhibited a positive correlation with PSA (β = 0.0005, 95% CI: (0.0002, 0.0007)), and an interaction test indicated that the effects of age, body mass index, hypertension, and diabetes were not significant for this positive correlation between SII and PSA (all P > 0.05). We discovered an inverted U-shaped connection between the SII and PSA with a turning point (K) of 1168.18 by using a two-segment linear regression model. To the left of the turning point, there was a positive connection between SII and PSA (β = 0.0009,95% CI: (0.0006, 0.0012); P < 0.0001). Conclusion: In the population of men over 40 years old without prostate cancer, SII and PSA exhibited a non-linear relationship. Specifically, there was a positive correlation between SII and PSA levels when the SII value was < 1168.18. [ABSTRACT FROM AUTHOR]