Background: In Chinese culture, smoking can promote social connectedness and integration. We therefore hypothesized that smoking would be negatively associated with loneliness in China. Given that loneliness is common and associated with adverse academic and health outcomes in university freshmen, examining correlates of loneliness in this population may deepen our understanding on the etiology of loneliness. This study investigated the association between smoking and loneliness in Chinese university fresh students. Methods: In this cross-sectional study, by using a two-stage cluster sampling approach, we recruited a total of 1,452 fresh students from a comprehensive university in Wuhan, China. These students completed a self-administered questionnaire containing the Chinese six-item De Jong Gierveld Loneliness Scale (DJGLS) and standardized questions on socio-demographics, internet use, and substance use, including smoking and use of alcohol and illicit drugs. Multiple linear regression was used to test the independent association of loneliness with smoking. Results: In Chinese university freshmen, current smokers had significantly higher DJGLS scores than non-smokers (11.9 +/- 4.60 vs. 8.53 +/- 3.72, t=7.351, P<0.001). After controlling for socio-demographic variables, current drinking, lifetime illicit drug use, and daily hours of internet use, the positive association between current smoking and DJGLS score remained statistically significant (unstandardized coefficient: 3.053, P<0.001). Conclusions: Smoking is independently and positively associated with loneliness in Chinese university freshmen. Smoking cessation might be helpful for preventing and reducing loneliness among Chinese university fresh students.