Tobacco inhalation is one of the major causes of mortality and morbidity worldwide. Tobacco can be smoked in many different ways, including cigarettes, cigars, pipes and hookah. Cigars are defined as “any roll of tobacco wrapped in leaf tobacco or any substance containing tobacco” and cigars that weigh less than three pounds per one thousand units are identified as “Little Cigars” and often have less stringent regulation that cigarettes. Although the deleterious effects of cigarette smoking have been widely documented, little is known about the health effects of related tobacco products such as little cigars. We exposed well differentiated, primary human bronchial epithelial cells cultured at the air liquid interface to air or freshly generated smoke from either Kentucky research cigarettes, two leading brands of little cigars (Swisher Sweets and Captain Black) and one brand of cigar (Cheyenne; that is of similar size to little cigars) and evaluated general cytotoxicity and CFTR-dependent airway hydration. All experiments were performed on replicate cultures obtained from a minimum of 5 separate donors. Neither chronic cigarette smoke nor chronic cigar smoke exposure altered gross cellular morphology, but caused cytotoxic effects that were significantly greater with little cigar exposure than with Kentucky cigarette exposure, as evident by significantly greater LDH release (Air, 2.5±0.7, Kentucky, 5.6±1.2, Swisher, 11.7±2.3; n=12). Airway surface liquid height and CFTR protein levels were also significantly decreased in chronic little cigar-exposed cultures compared to Kentucky cigarette or air exposed cultures (Air, 6.9±0.2, Kentucky, 5.4±0.2, Swisher, 4.9±0.1; n=12). However, epithelial sodium channel levels were unaffected (n=5). A significantly greater decrease in transepithelial resistance also occurred with little cigar exposure (Air, 536±35, Kentucky, 438±31, Swisher, 355±32; n=12). Our GC-MS analysis indicated that compounds present in all groups were found in higher quantity in cigars relative to Kentucky cigarettes. Additionally, many more unique compounds were identified in cigars that were not present in Kentucky cigarettes, suggesting that cigars expose the lung to different and potentially more harmful toxicants. In conclusion, our data indicate that little cigar/cigar smoking causes severe airway dehydration and ciliary dysfunction that is predicted to trigger pulmonary disease that may be more harmful than that seen with cigarette smoking. These changes are caused by the increased number of chemical species present in the tar phase of cigars.