Background: Coronary artery disease (CAD) is showing an increasing trend in young adults. Cigarette smoking has been shown to be a major cause of premature CAD. Previous studies have also shown that hyperuricemia (HUA) is associated with CAD; however, the interaction effect between HUA and smoking on CAD is uncertain. Therefore, this study was designed to determine the relationship and interactive effects of HUA and smoking on the risk of CAD in young adults <= 35 years of age. Methods: In this observational study we consecutively included adults (18-35 years of age) with suspected CAD who underwent coronary angiography for the first time in our institution from January 2005 to December 2015. Patients with stenosis affecting >= 50% of the luminal diameter and acute myocardial infarction were considered to have CAD. A serum uric acid (SUA) level >= 7.0 mg / dl (420 mmol / L) in males and >= 6.0 mg / dl (357 mmol / L) in females was defined as hyperuricemia. We tested for an interaction between HUA and cigarrete smoking on CAD. The relationship between HUA, cigarrete smoking, and CAD was assessed by multivariate logistic regression analysis. Results: A total of 1113 participants were included in this study; 771 participants were confirmed to have CAD. HUA was present in 34.8% of the participants. HUA was significantly higher in the CAD group (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.02-1.76; p = 0.035). More smokers were in the CAD group (OR, 1.59; 95% CI, 1.22-2.07; p = 0.001). Based on multivariate regression analysis and after adjustment for age, BMI, high LDL-C level, low HDL-C level, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome, diabetes mellitus, and hypertension, HUA was shown to be strongly associated with the presence of CAD in non-smokers (OR, 1.84; 95% CI, 1.03-3.29; p = 0.039). We further demonstrated that the interaction between HUA and cigarrete smoking achieved statistical significance for the presence of CAD (p = 0.008). Conclusions: In the current study, HUA was shown to be associated with the presence of CAD in non-smokers <= 35 years of age.