INTRODUCTION Waterpipe tobacco smoking is increasing in popularity though the toxicant exposure and effects associated with this tobacco use method are not well understood. METHODS Sixty-one waterpipe tobacco smokers (56 males; mean age +/- SD, 30.9 +/- 9.5 years; mean number of weekly waterpipe smoking episodes, 7.8 +/- 5.7; mean duration of waterpipe smoking 8.5 +/- 6.1 years) abstained from smoking for at least 24 hr and then smoked tobacco from a waterpipe ad libitum in a laboratory. Before and after smoking, expired-air carbon monoxide (CO) and subjective effects were assessed; puff topography was measured during smoking. RESULTS The mean waterpipe use episode duration was 33.1 +/- 13.1 min. Expired-air CO increased significantly from a mean of 4.0 +/- 1.7 before to 35.5 +/- 32.7 after smoking. On average, participants took 169 +/- 100 puffs, with a mean puff volume of 511 +/- 333 ml. Urge to smoke, restlessness, craving, and other tobacco abstinence symptoms were reduced significantly after smoking, while ratings of dizzy, lightheaded, and other direct effects of nicotine increased. DISCUSSION Expired-air CO and puff topography data indicate that, relative to a single cigarette, a single waterpipe tobacco smoking episode is associated with greater smoke exposure. Abstinent waterpipe tobacco smokers report symptoms similar to those reported by abstinent cigarette smokers, and these symptoms are reduced by subsequent waterpipe tobacco smoking. Taken together, these data are consistent with the notion that waterpipe tobacco smoking is likely associated with the risk of tobacco/nicotine dependence.