The systemic immune-inflammation index (SII) is a novel and integrated marker that has not been studied with prostate cancer. We aimed to ascertain the association between SII levels and prostate cancer. We utilized data from the 1999-2010 cycles of the National Health and Nutrition Examination Survey (NHANES). Multivariate logistic regression analyses were conducted to evaluate the relationship between SII and prostate cancer. Additionally, subgroup analyses stratified by age, BMI, history of hypertension and diabetes were performed. A total of 8,020 participants were included in our analysis. After full adjustment, SII was associated with a 7% increased risk of prostate cancer (OR 1.07, 95% CI 0.99-1.15, p = 0.094). We further categorized SII values into three segments and found that individuals in the highest SII group had a 33% increased risk of prostate cancer than those in the tertile 1 group (OR 1.33; 95% CI 1.01-1.81; p = 0.044; P for trend = 0.046). In addition, a higher SII level was associated with a 137% increased risk of prostate cancer in the diabetes subgroup (OR 2.37; 95% CI 1.08-5.21; p = 0.031). The current study suggested that SII was positively associated with increased risks of prostate cancer. The SII might be an easily accessible indicator for identifying prostate cancer.