Folate deficiency is linked to serious birth defects, pregnancy complications, male infertility, cardiovascular diseases, and even the evolution of human skin color. Conflicting data exist on whether exposure to sun or artificial UV sources may deplete the levels of blood folate in humans. Blood contains several photosensitizers and proteins, as well as antioxidants, which when exposed to UV radiation and visible light may be involved in the degradation of folate. In this study the photodegradation of 5-methyltetrahydrofolate (5MTHF) in aqueous and deuterious solutions exposed to UVB, UVA, or visible light in the absence or presence of riboflavin, uroporphyrin, and conjugated bilirubin was investigated by absorption spectroscopy. 5MTHF is stable under exposure to visible light and UVA radiation, whereas it is slowly photooxidized under UVB exposure. However, it is rapidly oxidized by UVA or visible radiation in the presence of riboflavin or uroporphyrin, but not in the presence of conjugated bilirubin, which acts in a protective manner. Reactive oxygen species produced in type I and/or type II reactions were involved. This study suggests that 5MTHF in blood can be photodegraded in the presence of the flavins and porphyrins, but protected by bilirubins. This may have health and evolutionary implications.