ABSTRACT The 2014 Surgeon General's report indicated that there was suggestive evidence demonstrating that ventilated filters have played a role in the increased incidence of lung adenocarcinoma. In a more recent weight of evidence review by us, including an in-depth analysis of biological plausibility, we concluded that there was highly suggestive evidence that filter ventilation paradoxically increased the risk of lung adenocarcinoma, while other lung cancers decreased with decreasing smoking prevalence. This increase in risk is based on how ventilation alters the way the cigarette burns and the elasticity of the cigarette that allows greater delivery of nicotine and harmful smoke constituents to the peripheral parts of the lung, where adenocarcinomas more commonly occur. A strong case can be made for the FDA to consider regulating filter ventilation, including a ban, based on the increasing incidence of adenocarcinoma, enhanced toxicant exposures, misperceptions about the relative safety of these cigarettes and increased abuse liability resulting from the cigarette's elasticity. However, to date, there are no studies on the impact of removing filter ventilation on smoking behavior and resultant exposures and toxicity. Therefore, the primary goal of this project is to assess this, and importantly to do so in the context of an experimental marketplace that allows and does not allow access to alternative nicotine delivery systems (ANDS; e.g., e-cigarettes, smokeless tobacco and nicotine replacement therapy). Secondary aims include studying the predictors of exposure and the type and characteristics of ANDS that are chosen. The study design is a 2 x 2, in which smokers will be randomized (N=125 in each of 4 conditions and 20% dropout rate for final N=400) to ventilated or unventilated cigarettes, with and without access to ANDS. Both validated exposure and novel biomarkers (e.g., metabolomics and gene expression) collected in urine, blood, and lung will be analyzed during the course of the study. Smoking behavior will be assessed by puff topography and inhalation. We hypothesize that subjects using unventilated cigarettes will experience: 1) fewer cigarettes smoked; 2) less toxicant exposure and effect; 3) less smoking intensity and depth of inhalation; and 4) greater number of days abstinent from cigarettes, with greater effects observed among those smokers with access to ANDS. Furthermore, the predictors of cigarette use and exposure biomarkers will be dependent on cigarette type, access to ANDS, consumer perceptions and response to the cigarettes, demographic and smoking history variables. The type of product chosen will likely be e-cigarettes with higher nicotine doses and that are flavored. This project is innovative because it is the first to explore the effects of unventilated vs. ventilated cigarettes on a broad range of biomarkers, including ones that target the lung specifically, and within the context of a marketplace with ANDS. It is significant because it will provide the FDA information on whether or not there might be any unintended consequences if cigarette filter ventilation was eliminated.