The article describes how the idea of “naturalness” was used by three different groups in arguments over the risk of livestock vaccines developed in synthetic biology. Based on interviews with two groups of scientific experts and focus groups with lay people in five European countries, and using Toulmin’s argument analysis as the analytical tool, the article maps and compares the different ways in which “naturalness” was used as a warrant. Several notions of “naturalness” are involved in lay people’s reasoning and several lay people’s understandings of risk relied on their perceptions of the “unnaturalness” of the synthetic vaccines. The notion of “naturalness” was used less by synthetic biology experts and not at all by vaccine experts. Lay people see the vaccine as less natural than other vaccines and therefore as a greater risk. In contrast, synthetic biology experts understand synthetic biology as natural, and relate naturalness, unpredictability and risk.