Background: Acute effects of UV irradiation include UV-induced erythema. Sunlight plays an important role in the development of skin cancer. Several predictive factors of UV-induced erythema could also be predictive for skin cancer. Objective: Our objective was to quantitatively assess phenotypical and nutritional determinants of sensitivity to UV irradiation, as assessed by the minimal erythema dose (MED). Design: We conducted a cross-sectional study among 335 volunteers. Sensitivity to UV irradiation was established through assessment of the MED. Phenotypical determinants, including skin melanin content, hair color and iris color were determined by skin reflectance spectrometry, a subjective questionnaire and an objective classification system, respectively. Furthermore, dietary exposure was measured by carotenoids, vitamin C, retinol and α-tocopherol in serum. Results: Male subjects were found to be more sensitive to UV irradiation; that is, the MED was significantly lower compared to female subjects. Skin melanin content, which was positively associated with iris color in both sexes and with hair color in men, was the main phenotypical determinant of sensitivity to UV irradiation. No associations were found between serum carotenoids and MED in the total study group. Vitamin C was inversely associated with MED. However, associations between carotenoids concentrations and MED showed a positive trend in subjects with melanin values above and a negative trend in subjects below the median after adjustment for gender and total cholesterol. Conclusions: Skin melanin content and gender are important determinants of sensitivity to UV irradiation. No relation was found between serum carotenoids and MED in the total study group. The inverse association between vitamin C and MED was against our hypothesis. For the modifying effect of melanin on the association between carotenoids and MED, we do not have a clear biological explanation.