The influence of inhalation depth and breath-hold duration on the retention of nicotine and solanesol in the human respiratory tract and on nicotine uptake was studied in ten cigarette smokers. In a first series of experiments, the subjects took seven puffs from a 10 mg 'tar' yield, test cigarette and a fixed volume of air (0, 75, 250, 500 or 1000 mL, as required by the protocol) was inhaled after each puff in order to give a controlled 'depth' of inhalation. The inhalation was drawn from a bag containing the required volume of air. Following a 2 s breath-hold, subjects exhaled normally, with the first exhalation after each puff passing through a single acidified filter pad for collection of the non-retained nicotine and solanesol. Blood samples were taken before and at intervals during and after smoking for the sessions with 0, 75 and 500 mL inhalation volumes for determination of plasma nicotine and carboxyHb levels. Another series of experiments was conducted with a fixed inhalation volume (500 mL) and two further breath-hold durations (0 and 10 s) in addition to 2 s from above. Nicotine and solanesol retentions were measured for each breath-hold condition. The amounts of nicotine retained within the respiratory system, expressed as a percentage of the amount taken into the mouth, were consistently higher than the corresponding values for solanesol in all five inhalation conditions (0-1000 mL, 2 s breath-hold). Nicotine retention increased from 46.5% at zero inhalation to 99.5% at 1000 mL inhalation (2 s breath-hold) and from 98.0% at zero breath-hold to 99.9% at 10 s breath-hold (500 mL inhalation). Solanesol retention increased from 34.2% at zero inhalation volume to 71.9% at 1000 mL inhalation (2 s breath-hold) and from 51.8% at zero breath-hold to 87.6% at 10 s breath-hold (500 mL inhalation). Plasma nicotine decreased from pre-smoking levels after zero inhalation indicating that the nicotine retained within the mouth was poorly absorbed into the systemic circulation. After 75 mL inhalation, plasma nicotine levels were significantly greater than for zero inhalation but not significantly less than after 500 mL inhalation except at the time of maximum nicotine concentration As in every exptl. condition, a higher percentage of nicotine than solanesol was retained within the respiratory tract, it was concluded that the difference in retention of the moderately volatile nicotine and the non-volatile solanesol is consistent with the concept of nicotine evaporation from smoke particles and the subsequent efficient retention in the airways of gaseous nicotine. The retention of solanesol followed the expected pattern of particulate deposition i.e., an increase with both increasing depth of inhalation and breath-hold duration. However, nicotine retention was almost complete even at shallow inhalations and short breath-hold durations.