Exposure to ultraviolet (UV) radiation, as in sunlight, can modulate immune responses in animals and humans. This immunomodulation can lead to positive health effects especially with respect to certain autoimmune diseases and allergies. However, UV-induced immunomodulation has also been shown to be deleterious. Experimental animal studies have revealed that UV exposure can impair resistance to many infectious agents, such as bacteria, parasites, viruses, and fungi. Importantly, these effects are not restricted to skin-associated infections, but also concern systemic infections. The real consequences of UV-induced immunomodulation on resistance to infectious diseases are not known for humans. Risk estimations have been performed through extrapolation of animal data, obtained from infection models, to the human situation. This estimation indicated that UV doses relevant to outdoor exposure can impair the human immune system sufficiently to have effects on resistance to infections. To further quantify and validate this risk estimation, data, e.g., from human volunteer studies, are necessary. Infection models in humans are not allowed for ethical reasons. However, vaccination against an infectious disease evokes a similar immune response as the pathogen and thereby provides an opportunity to measure the effect of UV radiation on the immune system and an estimate of the possible consequences of altered resistance to infectious agents. Effects of controlled UVB exposure on immune responses after hepatitis B vaccination have been established in mice and human volunteers. In mice, cellular and Th1-associated humoral immune responses to hepatitis B were significantly impaired, whereas in human volunteers no significant effect of UVB on these responses could be found. Preliminary data indicate that cytokine polymorphisms might be, at least in part, responsible for interindividual differences in immune responses and in susceptibility to UVB-induced immunomodulation. In addition, adaptation to UV exposure needs to be considered as a possible explanation for the difference between mice and humans that was observed in the hepatitis B vaccination model.