BACKGROUND Waterpipe (hookah, shisha) tobacco smoking has spread worldwide. Many waterpipe smokers believe that, relative to cigarettes, waterpipes are associated with lower smoke toxicant levels and fewer health risks. For physicians to address these beliefs credibly, waterpipe use and cigarette smoking must be compared directly. OBJECTIVE The purpose of this study is to provide the first controlled, direct laboratory comparison of the toxicant exposure associated with waterpipe tobacco and cigarette smoking. METHODS Participants (N=31; M=21.4 years, SD=2.3) reporting monthly waterpipe use (M=5.2 uses/month, SD=4.0) and weekly cigarette smoking (M=9.9 cigarettes/day, SD=6.4) completed a crossover study in which they each smoked a waterpipe for a maximum of 45 minutes, or a single cigarette. Outcome measures included expired-air carbon monoxide (CO) 5 minutes after session's end, and blood carboxyhemoglobin (COHb), plasma nicotine, heart rate, and puff topography. Data were collected in 2008-2009 and analyzed in 2009. RESULTS On average, CO increased by 23.9 ppm for waterpipe use (SD=19.8) and 2.7 ppm for cigarette smoking (SD=1.8), while peak waterpipe COHb levels (M=3.9%, SD=2.5) were three times those observed for cigarette smoking (M=1.3%, SD=0.5; p's<0.001). Peak nicotine levels did not differ (waterpipe M=10.2 ng/mL, SD=7.0; cigarette M=10.6 ng/mL, SD=7.7). Significant heart rate increases relative to pre-smoking were observed at 5, 10, 15, 20, 25, and 35 minutes during the cigarette session and at 5-minute intervals during the waterpipe session (p's<0.001). Mean total puff volume was 48.6 L for waterpipe use as compared to 1.0 L for cigarette smoking (p<0.001). CONCLUSIONS Relative to cigarette smoking, waterpipe use is associated with greater CO, similar nicotine, and dramatically more smoke exposure. Physicians should consider advising their patients that waterpipe tobacco smoking exposes them to some of the same toxicants as cigarette smoking and therefore the two tobacco-smoking methods likely share some of the same health risks.