Background: Smoking persists as a global health problem being one of the major risk factors to non-communicable diseases and early death particularly among youth. However little is known about smoking impact on person's HRQOL. Objectives: This study aimed to determine the prevalence of tobacco smoking among Benha University students; assess the relationship between smoking behavior and their QOL and recommend a program for prevention smoking and control of related adverse health effects. Methods: This cross- sectional study was conducted on 771 students from four colleges of Benha University. Information on sociodemographic data, smoking behavior and Nicotine dependence was collected using a self-administered questionnaire. HRQOL was measured using SF-36 questionnaire. Multiple linear regression analysis was used to assess the most important predictors for HRQOL domains. Results: The prevalence of ever smoking was 43.7% while current smoking was 39.4%. Current smokers were older than never smokers (P 0.001). Students who were males, from urban areas and of middle social class were current smokers at higher percentage than former and never smokers (P= 0.001). Comparing with never smokers, current smokers had lower score means for general health perception, physical functioning, bodily pain and mental health scales; among former smokers, lower scores were observed in physical functioning, social functioning and bodily pain (P