BACKGROUND: Testosterone deficiency (TD) is a globally recognized health concern, closely linked to disruptions in uric acid and lipid metabolism. Recently, the uric acid to high-density lipoprotein cholesterol ratio (UHR) has emerged as a comprehensive index for assessing the impact of inflammation and metabolic disturbances on disease risk. Therefore, we intended to explore the association of UHR with total testosterone levels and the risk of TD among US male adults. METHODS: The analysis was based on data from the National Health and Nutrition Examination Survey (NHANES) conducted between January 2011 and December 2016. All eligible participants were males aged 20 and older who had complete data for UHR and testosterone levels. The associations between UHR and total testosterone levels and the risk of TD were examined using weighted multivariable linear and logistic regression analysis, respectively. To visually demonstrate the linear relationship between them, weighted regression using generalized additive models and smooth curve fits were applied. Furthermore, subgroup analyses with interaction tests were executed to evaluate the stability of the outcomes. RESULTS: Finally, a total of 2,844 men were enrolled in the study with the weighted mean age of 47.72 ± 0.42 years. Of these, 592 were diagnosed with TD. After controlling for potential confounders, the continuous UHR exhibited a positive linear correlation with the risk of TD (OR = 1.08, 95%CI: 1.04-1.11, P <
0.001) and a negative linear correlation with total testosterone levels (β=-7.82, 95%CI: -10.47 to -5.17, P <
0.0001). When UHR was categorized into quartiles, with Q1 as the reference, participants in Q4 had significantly lower total testosterone levels (β = -96.64, 95% CI: -129.39 to -63.90, P <
0.0001) and a higher risk of TD (OR = 2.35, 95%CI: 1.45-3.80, P = 0.001). These associations remained stable in subgroup analyses without significant interaction (all P for interaction >
0.05). CONCLUSIONS: The study indicates that, among adult males, higher UHR is negatively correlated with total testosterone levels and positively associated with the risk of TD. This suggests its potential value for early disease diagnosis and intervention. However, further clinical studies are needed to validate these findings.