The racemic mixture, [6RS]-5-formyltetrahydrofolate, is widely used clinically. In human subjects, orally-administered pure unnatural C-6 isomers, [6R]-5-formyltetrahydrofolate and [6S]-5,10-methenyltetrahydrofolate, were recently shown to be metabolized to the natural isomer, [6S]-5-methyltetrahydrofolate. We re-analysed the data from human studies published during the past four decades in which oral doses (≤10 mg) of racemic mixtures of these folates were used. We re-evaluated the data to determine whether these racemic mixtures are only 50 % bioactive or, as we now predict, more than 50 % bioactive. Our analyses indicate that, in human subjects, oral doses of the racemic mixture of the two formyltetrahydrofolates are 20–84 % more bioactive than would be predicted. These data are consistent with the following pathway: chemical conversion of these folates to 10-formyltetrahydrofolate; oxidation of 10-formyltetrahydrofolate to 10-formyldihydrofolate; subsequent enzymic conversion of 10-formyldihydrofolate to dihydrofolate by 5-amino-4-imidazolecarboxamide ribotide transformylase; and finally the well-established metabolism of dihydrofolate to [6S]-5-methyltetrahydrofolate. An additional review of the literature supports the in vivo oxidation of 10-formyltetrahydrofolate occurring to a certain extent, as 10-formyl-folic acid is rapidly formed after the administration of folic acid (pteroylglutamic acid) or 5-formyltetrahydrofolate in human subjects. The dogma that an oral dose of the unnatural C-6 isomer of 5-formyltetrahydrofolate is not bioactive in human subjects does not withstand scrutiny, most probably due to the previously unrecognized in vivo oxidation of 10-formyltetrahydrofolate. This discovery unveils new folate metabolism in human subjects.