Endogenous antioxidants are decreased in skin and blood during UV exposure. Combined supplementation of β-carotene, α-tocopherol and ascorbic acid in addition to topical sunscreens may help to lower the risk of sunburning. Acute UV erythema with sunburn reaction are the most important factors in conjunction with the cumulative life-long UV dose for inducing skin damage resulting in photoageing and precancerous and cancerous lesions. Therefore, a clinical, randomized, double-blind, parallel group, placebo-controlled study was conducted in healthy young female volunteers (skin type II) investigating the preventive, photoprotective effect of supplementation with Seresis®, an antioxidative combination containing both lipid and water-soluble compounds: carotenoids (β-carotene and lycopene), vitamins C and E, selenium and proanthocyanidins. In this study, the oral administration of Seresis appeared to be well tolerated. The preparation contains antioxidant compounds in quantities occurring at physiological levels and can therefore be used safely over a long period of time. Despite the fact that the assessment of the light sensitivity (minimal erythemal dose, chromametry) of the skin did not show any statistically significant differences between the Seresis and the placebo group, a clear statistical trend, however, could be demonstrated, i.e. Seresis was able to slow down the time of the development and grade of UVB-induced erythema. The primary efficacy parameter matrix metalloproteinases 1 (MMP-1) between treatment and placebo group following UV irradiation showed a significant difference (p < 0.05), which occurred due to the fact that after a 2-week UV irradiation, MMP-1 slightly increased (p < 0.03) in the placebo group and decreased (p < 0.044) in the treated group. The MMP-9 changes showed a clear tendency of decrease in the Seresis group (p < 1.393) and increase (p < 0.048) in the placebo group. These data emphasise that supplementation with Seresis decreases the UV-induced expression of MMP-1 and 9, which might be important in photoprotective processes. From our data, we thus finally draw the conclusion that by the combination of antioxidants, such as in the formulation of Seresis, a selective protection of the skin against irradiation can be achieved. This might be important for future recommendations for immediate suppression of the early phase of UV-induced erythema, that means pharmacological prevention of sunburn reaction as well as subsequent chronic skin damage.