Objective: There are limited data on the acute effects of water-pipe tobacco smoking, commonly known as water-pipe smoking (WPS), on cardiopulmonary parameters. This study evaluated the acute effects of a single 30-min session of WPS on carboxyhemoglobin (COHb) levels, pulmonary function test results, vital signs, fractional exhaled nitric oxide (FENO) levels, and exhaled breath condensate (EBC) cytokine levels in volunteers in a domestic, open-air, group smoking setting. Methods: This prospective study evaluated the above-noted outcome parameters before and after 30 min of WPS. The primary outcome parameter was the change in COHb levels. Results: Forty-five volunteers (30 men, 15 women), aged 32.35 ± 15.33 years, were recruited. After one session of WPS, the COHb levels rose significantly, from 1.47% ± 0.57% (median 1.4) to 9.47% ± 5.52% (median 7.4), P<.001. Systolic and diastolic BP levels significantly increased after smoking (systolic, 119.52 ± 12.07 mm Hg vs 131.98 ± 17.8 mm Hg; diastolic, 74.84 ± 7.89 mm Hg vs 82.98 ± 12.52 mm Hg, respectively; P<.001). Heart rates increased from 80.39 ± 9.92 beats/min to 95.59 ± 17.41 beats/min, P<.001; and respiratory rates increased from 14.36 ± 1.63 breaths/min to 16.68 ± 2.24 breaths/min, P<.001. There were decreases in forced expiratory flow between 25% and 75% of FVC, peak expiratory flow rate, F ENO levels, percentage of eosinophils in peripheral blood, and 8-isoprostane levels in EBC. Conclusions: This study shows that one session of WPS causes acute biologic changes that might result in marked health problems. It adds to the limited evidence that WPS is harmful and supports interventions to control the continuing global spread of WPS, especially among youth. Trial registry: ClinicalTrials.gov; No.: NCT01157832; URL: www.clinicaltrials.gov.