Background: Smoking and physical inactivity constitute a major public health concern for Greece. The purpose of this study was to examine smoking behaviour and physical activity (PA) in Greek health science students. Methods: A standardised questionnaire and the Greek version of IPAQ-short were given to 2000 health science students, randomly selected from five higher education institutions, in order to record smoking behaviour and PA status. All healthy young adults aged 19-30 years old were eligible. The final cohort size of the study was 1651 students (690 men). Results: In the overall population, smoking prevalence was 37.6%, with 23.1% being heavy smokers (≥21 cig/day). Smoking prevalence did not differ significantly between sexes, but heavy smoking was more prevalent in males. Age at smoking initiation was negatively associated with the daily number of cigarettes smoked (smoking volume), but only in females. The prevalence of health-enhancing PA (high PAclass) was only 14.2%, while 45.4% of the study population was classified as insufficiently active (low PAclass). Males were more physically active than females. Logistic regression analysis showed a strong inverse association between smoking and PA that was more pronounced in males. Smoking was associated with significantly decreased odds of being either moderately or highly physically active. Smoking volume was also negatively related with PA, but this relation was more pronounced in females. Conclusion: Smoking prevalence and rates of physical inactivity are considerably high in Greek health science students. Smoking was strongly and inversely associated with PA in this sample of Greek young adults.