Food additives can be regarded as the safest constituents of our daily food. Nevertheless, complicated issues with respect to their safety evaluation do also occur. In this review paper, some of these issues are illustrated by the description and evaluation of the research on the immunotoxicity of the food additive Caramel Colour III. Caramel Colour III is commonly used as a color additive in many products for human consumption. Toxicity studies conducted in the seventies demonstrated that administration of Caramel Colour III can cause a reduction in total white blood cell counts in rats, due to reduced lymphocyte counts. Studies reviewed in this paper demonstrated several other effects of Caramel Colour III on the immune system of rodents, including disturbed immune functions and changed resistance in infection models. In addition, studies in rats demonstrated that most of the effects occur only when the animals are fed a diet low in vitamin B6. The imidazole derivative 2-acetyl-4(5)-(1,2,3,4-tetrahydroxy-butyl)-imidazole (THI) was found to be responsible for the immunotoxicity. Issues such as the mechanism of action of THI and the role of vitamin B6 are discussed. Finally, the results of a human intervention study and the observed effect levels of THI in rats are discussed in terms of safety of the use of Caramel Colour III in our daily food supply.