Given U.S. Food and Drug Administration (FDA) regulation of tobacco products via the Family Smoking Prevention and Tobacco Control Act, there is a growing recognition of the need for evidence to assist both applicants and the FDA in making determinations of whether certain products may raise different questions of public health or are appropriate for the protection of public health. Quantitative risk assessment (QRA) is a useful tool to quantify relative public health impact. QRA was used to estimate cancer risk and cardiovascular, respiratory and reproductive or developmental toxic effects for conventional combustible cigarettes, heat-not-burn (HNB) cigarettes, and electronic cigarettes (e cigarettes). Machine-generated yields of several harmful and potentially harmful constituents (HPHCs) specified by FDA in mainstream smoke or aerosol were obtained from the literature for representative products from the three different categories of tobacco products. Potential health risks were evaluated following the standard QRA process, utilizing toxicity values from regulatory sources and standard default exposure factors from the U.S. Environmental Protection Agency and FDA, supplemented with assumptions to develop estimates of lifetime exposures. Emissions of HPHCs from HNB and e cigarettes were considerably lower than those from cigarette smoke. Compared with conventional cigarettes and assuming comparable usage patterns, reductions in cancer risk were estimated to be 69 % for HNB and 99 % for e cigarettes. In addition, reductions of 20 % to 99 % of cardiovascular, respiratory, and reproductive or developmental effects were estimated for HNB and e cigarettes. These results demonstrate that estimated lifetime health risks are lower for HNB and much lower for e cigarettes than those associated with smoking conventional cigarettes. Based on these findings, substituting conventional cigarette smoking with the use of HNB products or e cigarettes will substantially reduce exposure to tobacco-specific toxicants and may reduce risk of cancer and non-cancer health effects for the individual user.