Background/Aim: We evaluated the influence of smoking on head and neck squamous cell carcinomas (HNSCC), which are in their majority tobacco-driven. Tobacco smoke is expected to influence the expression of ABCG2-transporters involved in multidrug resistance. The aim of the study was to evaluate the effect of cigarette smoke condensate (CSC) on ABCG2 expression on HNSCC cells, to demonstrate the adverse effects of cigarette smoke during anticancer treatment in vitro and to assess the prevalence of ABCG2 expression in HNSCC. Materials and methods: HNSCC cell lines were treated with CSC and basal and induced ABCG2 expression was examined. The impact of CSC on cellular viability/proliferation during cytotoxic drug treatment was also evaluated. ABCG2 expression levels in HNSCC were correlated with the smoking history of patients. Results: HNSCC cells showed low basal ABCG2 expression. CSC treatment resulted in a threefold increase in the expression of ABCG2 and in resistance to cisplatin. Tumor samples of never smokers showed significantly higher ABCG2 expression compared to ever smokers. ABCG2 expression correlated with pack years of cigarette consumption. Conclusion: Tobacco consumption is linked to an inducible and increased ABCG2 protein expression and has an impact on drug resistance.