Background and Objective: Tramadol use is an overwhelming problem in Egypt. Males and females who use tramadol differ in their sociodemographic and clinical profiles. The aim of this study was to identify gender differences in tramadol use in students at Zagazig University, Egypt. Methods: A cross-sectional study included a total of 1135 undergraduate students, aged 17 to 34 years, from both sexes; males (n=674, 59.4%) and females (n=461, 40.6%), from 10 colleges in Zagazig University. Respondents were randomly selected to assess their tramadol use utilizing the drug use disorders identification test (DUDIT) and the drug use disorders identification test-extended (DUDIT-E). Results: Tramadol use was more prevalent in male than female students (19.7% vs. 2.4%). Both smoking and alcohol use were shared predictive factors for tramadol use in both sexes. The mean years of education and cannabis use predicted tramadol use in males, while only mean age predicted tramadol use in females. Among tramadol users, males were more likely than females to be smokers, polysubstance, and cannabis users, and to have a positive attitude toward tramadol use. Conclusions: Tramadol use was common among university students, with higher prevalence among males. Sex-related similarities and differences were present. Results can guide health policymakers to develop appropriate prevention and management strategies. Population-based longitudinal studies are warranted to explore the causal relationship between tramadol use and progression to other substances in both sexes.