Smokeless tobacco (ST) products have the potential to be used as a harm reduction method for cigarette smokers. These products can deliver significantly less toxicants than cigarettes, although they are not toxicant free nor harmless. It is important to examine potential health risks and benefits of these products. These two small pilot studies examined the effects of two different ST products (Exalt and Ariva) compared with medicinal nicotine, another potential harm reduction product. Dependent, healthy adult cigarette smokers, who were motivated to quit smoking, underwent 1 week of baseline smoking measurement. They were then asked to quit smoking and were randomly assigned to use either an ST product or a medicinal nicotine lozenge (MNL, Commit) for 2 weeks, then crossed over to use the other product for 2 weeks. In the last week, following the sampling phase, subjects could choose the product they wished to use. Assessments were made repeatedly during baseline cigarette use and throughout the 5 weeks of treatment. Outcome measures included biomarkers for tobacco exposure and subjective, physiological, and behavioral responses. Tobacco-specific carcinogen uptake was greater from Exalt than from the MNL, and was comparable between the MNL and Ariva. Physiological effects and subjective effects on withdrawal and craving were comparable among Exalt, Ariva, and the MNL. Ariva was preferred over the MNL, which was preferred over Exalt. With the exception of medicinal nicotine products, low-nitrosamine ST products have the greatest potential to result in reduced toxicant exposure compared with other combustible reduced exposure products and have promise for reducing individual risk for disease. However, the population effect of marketing of such products as reduced exposure/reduced risk is unknown. The need for further research in this area and regulation of tobacco products is evident.