In view of subacute inhalation studies with cigarette smoke at high concentrations, the toxic properties of combinations of carbon monoxide and nicotine were investigated. Treating rats with fresh diluted cigarette smoke in an inhalation chamber, we established a smoking schedule that resulted in a certain death rate after 13 days. The mortality under the experimental conditions was taken as a measure for the toxicity of different combinations of carbon monoxide and nicotine. Since the absorption and therefore the toxicity of nicotine is pH dependent, the factorial experiments were performed under two pH conditions. The first experiments were conducted between pH 6.5 and 6.9 and then between pH 6.6 and 7.8 where the higher pH is due to the addition of nicotine base to the cigarette filler. After extensive mathematical treatment of the data, the following results were established: (a) Equations for the dose-response surface of CO and nicotine were computed. (b) R2 values (square of the multiple correlation coefficient) for the respective dose-response surfaces were between 87% and 94%. (c) From the respective equations the dose-response surfaces were drawn in the form of several computer plots. From the equations it becomes evident that, under the experimental conditions, there are no synergistic effects between carbon monoxide and nicotine. A simple additivity of the toxic effects was therefore postulated. On the other hand, it has been demonstrated that smoke pH plays an important role, because only from alkaline smoke does the absorption of nicotine seem sufficiently rapid for it to add to the acute toxicity of CO. The total particulate matter apparently does not contribute significantly to the toxicity of the smoke aerosol.